1. Migraine in the Female Life Cycle
Headache Forum
October 2007
Lucy Vieira MD

2. 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

3. 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)
Peak Incidence males
Migraine with aura:
5yo (6.6/1000)
Migraine without aura:
10-11yo(10/1000)
Incidence: rate of new cases in a certain population in a certain period
Migraine begins earlier in males and migraine with aura begins earlier than migraine without aura
Other studies linked to medical diagnosis suggest lower incidence rates: have shown that the incidence of migraine highest in woman aged 10 to 49 with a peak incidence at age 20 to 29 (later peak reflects delay in diagnosis)
Stewart et. al Amer J Epidemiol 34:
– the reported age of migraine incidence in a prevalence study

4. Prevalence of Migraine
Before puberty: prevalence higher in boys
Until early adulthood incidence and prevalence continue to increase
Prevalence highest from yo. Prevalence is stable in the USA over time.
American migraine study-I- info from 15,000 homes in 1989
AMS-II – AMPP – 2005.
prevalence mig: 18%F 6%M
One can more than double the prevalence if include Probable migraine (one criteria missing).
During the female reproductive years, migraine is up to three times more common in women than in men of similar age. This sex difference is generally considered to be due to the additional hormonal trigger in women. In specialist clinics and in population based studies, 50% of women report an association between migraine and menstruation. The peak time for migraine is on or between 2 days before the start of menstruation and the first 3 days of bleeding.
Lipton Headache 38: Lipton Headache 41: Lipton Headache 45:

5. 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: Hu 1999 Arch Intern Med 159: Holmes 2001 Neurology 56(s 1):13-19

6. 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.

7. 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%
A1.1.1 Pure menstrual migraine without aura
Diagnostic criteria:
Attacks, in a menstruating woman, fulfilling criteria for 1.1 Migraine without aura
Attacks occur exclusively on day 1±2 (ie, days –2 to +3)1 of menstruation2 in at least two out of three menstrual cycles and at no other times of the cycle
Notes:
1. The first day of menstruation is day 1 and the preceding day is day –1; there is no day 0.
2. For the purposes of this classification, menstruation is considered to be endometrial bleeding resulting from either the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the case of combined oral contraceptives and cyclical hormone replacement therapy.
A1.1.2 Menstrually-related migraine without aura
Attacks occur on day 1±2 (ie, days –2 to +3)1 of menstruation2 in at least two out of three menstrual cycles and additionally at other times of the cycle
A1.1.3 Non-menstrual migraine without aura
A. Attacks, in a menstruating woman, fulfilling criteria for 1.1 Migraine without aura
Attacks have no menstrual relationship1
Note:
1. That is, they do not fulfil criterion B for A1.1.1 Pure menstrual migraine without aura or A1.1.2 Menstrually-related migraine without aura.
Comments:
This subclassification of 1.1 Migraine without aura is applicable only to menstruating women.
The importance of distinguishing between A1.1.1 Pure menstrual migraine and A1.1.2 Menstrually-related migraine is that hormone prophylaxis is more likely to be effective for pure menstrual migraine. Documented prospectively-recorded evidence, kept for a minimum of three cycles, is necessary to confirm the diagnosis as many women over-report an association between attacks and menstruation.
Menstrual attacks are mostly migraine without aura. In a woman who has migraine both with and without aura, migraine with aura does not appear to be associated with menstruation.
The mechanism(s) of migraine may be different with endometrial bleeding resulting from the normal menstrual cycle and bleeding due to the withdrawal of exogenous progestogens (as occurs with combined oral contraception and cyclical hormone replacement therapy). For example, the endogenous menstrual cycle results from complex hormonal changes in the hypothalamic-pituitary-ovarian axis resulting in ovulation, which is suppressed by use of combined oral contraceptives. Therefore research should separate these subpopulations. Management strategies may also differ for these distinct subpopulations.
There is some evidence that menstrual attacks, at least in some women, result from oestrogen withdrawal, although other hormonal and biochemical changes at this time of the cycle may also be relevant. If pure menstrual migraine or menstrually-related migraine is considered to be associated with exogenous oestrogen withdrawal, both codes A1.1.1 Pure menstrual migraine without aura or A1.1.2 Menstrually-related migraine without aura and Oestrogen-withdrawal headache should be used.
MacGregor EA Cephalalgia 1990 and 1996

8. Figure 117">
MacGregor, E. A. et al. Neurology 2006;67:

9. Chance of migraine 2.5X more during days 1-3 of the cycle
Figure 217">
Chance of migraine 2.5X more during days 1-3 of the cycle
Woman average age 43 with Menstrually related migraine and regular cycles filled out diary cards and took early morning urine samples for analysis.
Peak incidence when estrogen at nadir and lowest incidence when estrogen high.
Migraine was more likely to occur on day vs all other times of the cycle (RR 1.45 [95% CI 1.17 to 1.79], p ). Furthermore,
these attacks were more likely to be moderate or severe (RR 1.35 [95% CI 1.03 to 1.74], p 0.03) and associated with nausea (RR 1.46 [95% CI 1.04 to 2.00], p 0.03) or vomiting (RR 2.56 [95% CI 1.05 to 5.78, p 0.04). This supports the hypothesis of estrogen “withdrawal” triggering migraine. Migraine was significantly less likely during phases of rising estrogen. There was no significant association between migraine and ovulation.
As only luteal estrogen “withdrawal” but not ovulatory estrogen “withdrawal” was associated with migraine, we agree with the suggestion that a period of sustained high estrogen priming is a necessary precursor. It is likely that the chemical alteration more directly responsible for migraine is the effect of the changing hormonal environment on other biochemical and metabolic pathways, rather than a direct effect of sex hormones. Serotonin producing neurons are sensitive to the presence or absence of ovarian hormones. Fluctuating levels of estrogen and progesterone in the luteal phase of the menstrual cycle affect levels of brain serotonin and abnormalities of the serotonin system in menstrual migraine have been reviewed. Close interrelationships between estrogens and the brain neurotransmitters have also been confirmed,including the catecholamines, norepinephrine, dopamine, and the endorphins.
Stewart et al reported that attacks of MWoA were 2.04 times more likely during the first 2 days of menstruation, while attacks of MWA occurred with equal frequency throughout the menstrual cycle.
The most plausible theory to explain the pathophysiology of menstrual migraine is that of "estrogen withdrawal." The estrogen withdrawal theory was advanced by Somerville, who demonstrated that the intramuscular injection of estradiol valerate administered shortly before menstruation could delay the onset of menstrual migraine by artificially raising serum estradiol levels during the late luteal and early follicular phases of the menstrual cycle23,24 (Figure 2). Intramuscular administration of progesterone prior to menstruation did not affect the time of onset of menstrual migraine.25 He later administered an intramuscular injection of a short-acting estrogen preparation to menstrual migraineurs during the mid-follicular phase of the menstrual cycle, but this did not trigger an attack. This experiment suggested that several days of estrogen priming prior to estrogen withdrawal was necessary in order to provoke a migraine headache.26
MacGregor, E. A. et al. Neurology 2006;67:
MacGregor E.A. et al., Neurology 2004;63:351-53

10. Pathophysiology of this incr. Risk of Migraine
estrogen withdrawal – incr. Neuronal excitability
Prostaglandin release
Magnesium deficiency
Prostaglandins are released into the systemic circulation by a shedding endometrium during the perimenstrual time period secondary to the withdrawal of progesterone. Several lines of evidence suggest that "prostaglandin release" plays a role in the pathophysiology of menstrual migraine.30 First, migraine-like headaches can be triggered by injections of prostaglandin E2 in nonmigraineurs.31 Second, serum taken from women during menstruation and later infused back to them at a later time can induce headache.32 Third, medications that are prostaglandin inhibitors have been used to prevent menstrual migraine
Martin VT Headache 2006;46:3-23 and

11. Martin V et al., Headache 2006;46:365-86

12. Estrogen and neuronal excitability
There is an increase in the density of NMDA receptor containing synapses on these dendritic pines. (post-transcriptional). Dendritic spine density correlates with levels of circulating estradiol during the estrous cycle; decreased by oophorectomy. Also decreases inhibitory gaba interneurons boutons and synapses.
Progesterone first support the increase in excitatory spines then decreases them therefore counteracting the estrogen effects
Treatment with estradiol increases dendritic spine density in hippocampal neurons (female rat): incr. Excitatory input
Woolley CS et al.,J Comp Neurol. 1993:336:

13. Cell membrane receptors
Hormones have nuclear receptors that can impact the transcription of certain genes and have effects on the production and release and action of different neurotransmitters. Estradiol is generally pro-excitatory: reduce activity of glutamic acid decarboxylase (RLS) for GABA synthesis. Increases NMDA function (ca entry).
Receptors are localized to specific brain regions including cortex, brainstem nuclei and hippocampus and thereby play a role in other pain mechanisms.
At the level of the cell membrane: estradiol has direct excitatory effects by incr nmda mediated glu receptor activity (ALLOSTERIC MECHANISM).
Similar effects of excitability are seen in experimental epilepsy models where estrogen increases spikes.
Serotonin – 5ht content higher in female rodent and varies with estrous cycle. 5ht important in pain. 5ht2a receptor promotes release of NO in trigeminovascular system – vasodilatation – sensitization of nociceptive receptors. Estradiol tends to increase serotonergic tone.
Opiatergic system. Estrogen withdrawal associated with opiate withdrawal.
(progesterone metabolite)

14. Effects of estrogen on Purkinje cell response to glutamate
Estrogen recently reported to decrease the threshold of CSD in brain slices.
Migraine occurs during peak estrogen times – pregnancy, ovulation. BUT it also occurs with estrogen withdrawal – therefore there is something to do with direction and rate of change.
One group use rats – remove ovaries then give high dose estradiol for 14 days. Estrogen then withdrawn from one group and the other continued to take it. The withdrawal group showed a 30% increase in susceptibility to CSD (Kudo and moskowitz 2006)
Effects of estrogen on Purkinje cell response to glutamate
(female rats)
Smith Brain Res. 1988;475:

15. Summary
Estradiol receptors are also found on mito – incr energy production require for the neuroexcitatory effects of estrogen

16. Martin and Behbehani. Headache 2006;46:365-86

17. PNAS 2001: 98:
Spreading depression during aura (Hadjikhani – fMRI: PNAS 2001: 98:
The neurovascular unit: glu synapse, astrocyte, BV Moskowitz Ann Neurol 2004; 55:276-80
Ann Neurol 2004;55:276-80

18. Hormonal treatments-premenopausal woman
Goals:
-prevent drop in estradiol?
-produce anovulation?
-add estrogen or progesterone that may have preventative effects?
Somerville showed that migraine was prevented with late luteal estrogen but not progesterone supplementation (Neurology ).
Other approaches to limit fluctuations in steroids and in steroid receptor activation: GnRH agonists (leuprolide), blockage of estrogen receptors (tamoxifen given day –7 to +3): Neurology ), stabilization of estrogen receptor activation by continuous exposure to dopamine (bromocriptine: inhibits GnRH release and LH release: Neurology 1997:48: )

19. 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
Used Zolodex implants for medical ooporectomy then estradiol 100 microgram patch
After creation of a medical menopause, the headache index was found to be 39% lower in the GnRHa/estradiol group as compared to the GnRHa/placebo group. This suggests a preventive role for transdermal estradiol in this population. First, minimization of fluctuations in serum estradiol alone is insufficient to prevent headache in female migraineurs. Second, estradiol may have the ability to prevent and provoke headache. After induction of a medical menopause,
transdermal estradiol decreased headache compared both to a normal menstrual cycle and the treatment phase of the GnRHa/placebo group.
Martin V. Headache 2003;43:309-21

20. 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 pg/ml.
May cause spotting and irregular menses.
Migraine shifted to when take off gel/patch.
Granella F Cephalalgia 17:35-38, MacGregor A Neurology 2006; 67:

21. Figure 118">
We here report the results of a trial that aimed to assess the effect of perimenstrual estradiol on the occurrence of menstrual migraine when used in conjunction with a fertility monitor. By identifying peak fertility associated with ovulation, the monitor could predict menstruation and hence be used to indicate when to apply the gel. We also examined the association between urinary estrogen levels and migraine,and the effect of estradiol on the length of the follicular and luteal phases.
Because migraine is most likely to occur on or between 2 days before the start of menstruation and the first 3 days of bleeding
we considered that the optimal time to use the gels was from 6 days before the first full day of bleeding up to and including the second full day of bleeding. This allowed 3 days for a steady state to be reached after starting supplements and 3 days decline when gel was stopped, the latter allowing sufficient time for follicular phase endogenous estrogen levels to rise. The time period from the LH surge to menses is consistently
close to 14 days. Women calculated the start day for the gel by marking on their diaries the first day that they saw the peak fertility symbol on the monitor as day 1. They were instructed to start using the gel on day 10 (day of LH surge 9 days), approximating to 6 days before the first full day of bleeding. They were instructed to continue it daily until, and including, the second full day of bleeding of the next cycle. The incidence of short luteal phases in the normal population is about 5 to 6%. In line with this, two women were identified with short luteal phases during the three pretreatment cycles and the timing of estradiol was adjusted accordingly (6 and 8 days following the LH surge, in that order). The dispensing pump delivers unit doses of 0.5 g of gel containing 0.5 mg of estradiol or placebo. Three pump doses were used daily, i.e., 1.5 mg estradiol, applied to the upper arms or thighs.
Estradiol was associated with a22% reduction in migraine days per woman; RR 0.78 (95%CI 0.62 to 0.99). These attacks were also less severe (p 0.03) and there was evidence that they were associated with less nausea, although this difference was not significant. There was, however, evidence of an increase in migraine occurrence in the 5 days immediately following estradiol compared to placebo, RR Our results confirm that perimenstrual estrogen supplements can reduce the severity and duration of menstrual attacks of migraine during treatment. This is in keeping with other studies using a similar dose of estrogen to achieve serum estradiol levels of at least 60 pg/mL. Possible reasons for the occurrence of post-gel estrogen withdrawal migraine are that the dose of estradiol was inadequate; the duration of treatment was too short; or perhaps that exogenous estrogen inhibits the follicular rise of endogenous estrogen.This latter possibility is consistent with the observation that the follicular phase was 1 day longer in cycles in which estradiol was used
MacGregor, E. A. et al. Neurology 2006;67:

22. 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
Today’s low-dose OCs all contain the same estrogen component (ethinyl estradiol [EE]) but vary in the progestin component. Until recently, all progestins in OCs (norethindrone, levonorgestrel, desogestrel, and norgestimate) were derivatives of 19-nortestosterone. A novel OC with the progestin drosperinone (DRSP) is not derived from 19-nortestosterone, but instead derived from spironolactone. This DRSP-containing OC has been shown in a large placebo-controlled trial to significantly improve the physical and behavioral symptoms of premenstrual syndrome (PMS)
and premenstrual dysphoric disorder (PMDD)

23. Migraine and OCPs Unchanged in half, worse in 30% and improved in 6%
Patients with aura more likely to worsen (50% vs 25%)
Aura may develop for the first time with OCPs.
(1) most contraceptive trials do not demonstrate statistically significant differences in "headache complaints" between treatment and control groups, (2) women with a history of migraine or "troublesome" headaches may be at increased risk of "headache complaints" with OCPs, (3) the type and dosage of progestin does not influence headache activity, and (4) if headaches begin or worsen during the first month of OCP use, they will often improve during subsequent months. Cachrimanidou et al59 reported an incidence of headache complaints of 9.7% in participants receiving extended duration OCPs and % in those receiving standard OCPs.
Martin V. Headache 2006; 46:365-86

24. 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): Mousa Am J Optom Physiol Opt. 1982;59:821-23).

25. 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.

26. Phx: negative
Smoking: none
Neurological exam and blood tests normal.
How would you manage this patient?

27. 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): Tzourio C, Bousser MG. Stroke. 1997;28(12):
Tzourio C, et al.,BMJ. 1993;307(6899): Chang CL, et al., BMJ. 1999;318(7175):13-18.
Velentgas P, Headache. 2004;44(7):

28. No of studies Relative risk (95% CI) Ri* P value† Migraine (any)
Pooled rel. risks of stroke stratified by migraine type, oral contraceptive use, and age
No of studies Relative risk (95% CI) Ri* P value†
Migraine (any)
All studies (1.89 to 2.48)
Case-control studies (1.86 to 2.56)
Cohort studies (1.61 to 2.75)
Migraine with aura
Case-control studies (1.61 to 3.19)
Migraine without aura
Case-control studies (1.06 to 3.15)
Migraine among oral contraceptive users
Case-control studies (5.05 to 15.05)
Migraine among men and women <45 years
Case-control studies (1.92 to 2.90)
Migraine among women <45 years
Case-control studies (2.17 to 3.52)
*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
Etminan, M BMJ  2005;330:63 

29. 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.

30. Migraine as a risk factor for Stroke in young women (<45)
(Absolute risk is about 2/100000/year) RR
Migraine without aura 3
Migraine with aura 6
No aura + BCP* 6
Aura + BCP* 12
Aura + smoking 12
Aura + BCP* + smoking 35
Bousser, MG Stroke.2004;35(suppl I): *low estrogen+progesterone
Migraine is not correlated with increased stroke risk in postmenopausal women.
NO evidence of increased stroke risk in progesterone only pill.
BCPs should not be used in those with migraine aura or with cardiovascular risk factors.

31. 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.

32. 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

33. 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

34. 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

35. Acute Rx: triptans
Sumatriptan 100mg PO, 6mg s/c, rizatriptan, zolmitriptan, Naratriptan
All effective in placebo controlled trials

36. Short-term MM prophylaxisMg
360 mg/d
Day 15-menses
Naproxen
550 mg BID
Day -7 to +6
DHE-45 NS
NS q8h
Day -2* to +4
Estradiol gel
1.5 mg Qday
Day -2* to +5
Estradiol patch
100 mg
same
Sumatriptan
25 mg TID
day -2 to +3
Naratriptan
1 mg BID
Day -2 to +3
Zolmitriptan
2.5 mg BID
Day -2 to +4
Magnesium pyyrolidone carboxylic acid 360 mg/d from day 15 to menses
Decr. # HA days and total pain index vs placebo
Low brain magnesium levels have been reported in at least 8 studies involving migraineurs. At least 4 trials of magnesium as prophylactic therapy for migraine have been conducted, along with trials investigating magnesium as an acute treatment for migraine. The published trials have yielded mixed results, with favorable effects reported for acute treatment of patients with aura and, possibly, perimenstrual migraine prophylaxis. The magnesium formulation used has varied, and no study has compared different magnesium formulations with similar dosages of Mg++ to determine whether formulation type has clinical relevance. Magnesium's efficacy as an acute therapy may relate to ionized Mg++ levels, and it appears that prolonged "high dose" supplementation for a minimum of 3 to 4 months may be required to achieve any benefit from prophylactic therapy. Due to inconsistent findings from multiple trials, the evidence level for magnesium in prevention of migraine is Grade B.
Again, several reports have indicated that low levels of intracellular magnesium ion and serum ionized magnesium may correlate with the agent's efficacy, and the conflicting results from migraine treatment of subjects either likely to respond (low levels) or unlikely to respond (normal levels).[30-33] Even should this variable be adequately accounted for in future research, there is another that appears problematic. In a study designed to determine magnesium effects on sumatriptan nonresponders (83% of whom had low ionized magnesium levels), Cady et al found that although ionized magnesium levels could be normalized intravenously, a daily dose of 250 mg of oral magnesium taurate for 5½ months failed to maintain normal levels.[34] Mauskop has recommended a daily dose of 600 mg of chelated or slow-release oral magnesium for sustained supplementation.[35]
The first RCT of magnesium for migraine prevention involved only 20 subjects and was positive; the active therapy was 360 mg Mg++ pyrrolidone carboxylic acid divided TID.[30] The second RCT, by Peikert et al, involved 81 adult women and 600 mg magnesium (trimagnesium dicitrate) daily demonstrated a 41.6% improvement with verum versus 15.8% for placebo.[36] The third RCT for migraine prophylaxis, published by Pfafferath et al, involved 69 patients taking 486 mg magnesium; no benefit for magnesium was found; at the end of the 3-month treatment phase, the responder rate was 28.6% in the magnesium group and 29.4% in placebo subjects, according to the primary efficacy endpoint. Diarrhea was reported in significant numbers of both patients receiving placebo (23.5%) and patients receiving magnesium (45.7%); the high rate in the active arms suggests that a poorly absorbed magnesium preparation lent to the negative outcome.[37,38] In a last trial, Wang et al gave magnesium oxide 9 mg/kg divided TID to subjects aged 3 to 17 years.[39] Approximately three-quarters of eligible subjects completed the study, with a significant downward trend in headache days in the active treatment group versus placebo; the lack of any difference in the slope of treatment trends, however, was such that no significant superiority of magnesium over placebo could be documented.
Adverse events reported consequent to magnesium therapy have been mainly gastrointestinal (diarrhea predominating). There is no evidence of any short- or long-term safety issues for individuals taking magnesium in the absence of serious renal disease.
* Refers to before expected headache

37. 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: )

38. Extended duration OCPs
Sulak Headache 2007;47:27-37
Wanted to see the effect on headache of eliminating the placebo week where headaches tend to occur.
Methods.—An open label single-center prospective analysis of headaches recorded daily on a severity scale of 0 to 10, along with the headache item of the Penn Daily Symptom Rating (DSR17) and a weekly modified Migraine Disability Assessment (MIDAS) headache questionnaire, during standard 21/7-day cycles followed by a 168-day extended placebo-free regimen of an OC containing 3 mg of drosperinone and 30 mcg of ethinyl estradiol(contained 3 mg of DRSP and 30 μg of EE in each(Yasmin, Berlex Labs,)
Patients improved regardless of whether their headaches were more common during menstruation or not. Previous retrospective trials have shown that continuous OCPs are good for this.

39. 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.

40. 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.

41. 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)
Such a "hormonal milieu" might be provocative for migraine during the perimenopausal time period if higher levels or greater fluctuations in estrogen provoke migraine. If mid-luteal progesterone is preventative for migraine, then anovulation encountered during the perimenopause could be provocative for migraine

42. 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.

43. 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

44. 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): Granella F,. Headache. 1993;33(7):
The World Health Organization has defined menopause as the "permanent cessation of menstruation, determined retrospectively after 12 consecutive months of amenorrhea without any pathological or physiological cause. Menopause represents a time period during which women have depleted their supply of follicles from the ovaries resulting in a permanent cessation of ovulation. Serum levels of estradiol typically range from 10 to 20 pg/mL in most postmenopausal women. Postmenopausal women often experience symptoms such as hot flashes, fatigue, forgetfulness, loss of memory, inability to concentrate, anxiety, depression, irritability, and headache. Many of these symptoms can be improved with estrogen replacement therapy.

45. 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.
Pathogenesis.—"Estrogen withdrawal" and its effects on the central nervous system are thought to be the primary mechanism through which symptoms are provoked during the menopausal time period (eg, hot flashes, headaches, etc.). In fact, many of the same neurotransmitter systems altered during menstrual migraine secondary to "estrogen withdrawal" may also be affected by menopause. Decreased opioid tonus within hypothalamic nuclei, decreased blood serotonin levels, and up-regulation of certain serotonin receptors (eg, 5- HT 2A) have been demonstrated within studies of postmenopausal women

46. 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): Greendale GA, Obstet Gynecol. 1998;92(6): MacGregor A. Headache. 1999;39(9):

47. 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):
Facchinetti F Headache.2002;42(9):
Risk of HRT.—HRT does carry some risk to postmenopausal women. The Women's Health Initiative reported that oral conjugated estrogens administered daily along with a progestin significantly increased the risk of breast cancer (hazard ratio [HR], 1.26), stroke (HR, 1.41), pulmonary embolus (HR, 2.13), and coronary heart disease (HR, 1.29). This data has led several expert panels to discourage use of HRT for the prevention of chronic disease. They recommended HRT for short-term use (<2 years) during the early menopausal time period to manage symptoms of hot flashes, but to discourage long-term use for other indications.