Headaches in Women

Introduction

To a greater or lesser extent, hormones are probably involved in most headaches. Although other triggers have been mentioned, no other factor has been as closely linked to the pathophysiology of migraine in women as changes in serum estrogen levels. These changes in estrogen levels have been investigated more than any other trigger factors in migraine. Current thought recognizes that estrogen fluctuations serve as a trigger of migraine in women, but can also be used to prevent these headaches. In this section, we will focus on headaches as they affect the life stages of women:

• Menstrual periods
• Pregnancy
• Lactation
• Menopause.

We will also consider those headaches that are related to hormonal therapy in the form of:

• Oral contraceptives (OCs)
• Hormone replacement therapy (HRT).

Approximately 75% of all migraine sufferers are female, and about 70% of female patients with migraine describe a relationship between their headaches and their menstrual periods. They commonly experience headaches a few days before, during and immediately after the menses. Some will relate the onset of the headaches to menarche. Pregnant patients with migraine typically report that their headaches disappear after the third month of pregnancy. Postmenopausal women with migraine may notice a gradual decrease and then disappearance of the migraine attacks. Estrogen used in hormonal supplements and OCs is known to increase the frequency, severity, duration and complications of migraine.

Menstrual Headaches

The current classification of headache disorders, International Classification of Headache Disorders (ICHD-3), recognizes six types of menstruation-associated migraine: three types (pure menstrual migraine, menstrually related migraine and non-menstrually related migraine) each for migraine without aura and migraine without aura. The diagnostic criteria for these migraines are shown in Table 8-1. In studies of women with tension-type headache (TTH), menstruation has been identified as a precipitating factor. Some of these patients reported a cyclic influence, with an increase in frequency and seriousness during the premenstrual period.

Rapid fluctuations, particularly in the levels of estrogen and progesterone or changes in the estrogen/progesterone ratio, are considered to be the cause of menstrual migraine. It is these changes or variations in hormones that trigger the migraine attack in some women, in contrast to the stability of the hormones in men. Gonadotropin-releasing hormone (GnRH) activates the pituitary to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These two hormones stimulate the production of estrogen and progesterone by the ovaries, which signals the endometrium to produce prostaglandins.

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Premenstrual Headaches

Headaches that occur during the premenstrual part of women’s menstrual cycles can be diagnosed either as TTH or a combination of migraine and TTH. These patients may experience a wide range of other premenstrual syndrome (PMS) symptoms, both physical and emotional. Physical complaints include:

• Fatigue
• Joint pain
• Breast tenderness
• Fluid retention
• Food cravings.

Emotional manifestations include:

• Anxiety
• Depression
• Impaired judgment or memory
• Paranoia.

Pregnancy

In perhaps 70% of cases, the problem of migraines improves with pregnancy, probably because of sustained high estrogen levels. Even if headaches persist during the first trimester, they usually disappear during the second and third trimesters. One trial has found that up to 85% of women experience migraine remission during pregnancy.

Postpartum headache may be either migraine or TTH. Headaches can occur at any time during the first week postpartum, although they tend to cluster around days 4 to 6 postpartum. A strong association with a previous personal or family history of migraine is usually indicated. Migraines occurring in the postpartum period are related to the drop in estrogen and progesterone following delivery. These migraine attacks are described as milder than usual.

Some postpartum headaches coincide with weight loss beginning 3 or 4 days postpartum. In any case, headaches are known to be part of the postpartum depression complex that should be treated appropriately.

Lactation

Breast-feeding may provide some protection against migraine attacks, perhaps through increased vasopressin and oxytocin secretion, which is associated with antinociceptive properties. While there is little evidence for a change in migraine frequency during lactation, one study has found that postpartum recurrence of migraine is delayed in women who are breastfeeding (recurrence rates of 50% at 1 month, 65.8% at 3 months and 71.1% at 6 months) compared to those who are bottle-feeding (recurrence rates of 86.4% at 1 month, 90.9% at 3 months and 95.5% at 6 months).

Menopause

As menopause approaches, estrogen levels and fluctuations gradually decrease, and migraine attacks often decrease in frequency or cease with menopause. In some cases, however, migraine headaches can become worse or may occur for the first time in women vulnerable to hormonally-mediated vascular changes. Natural versus surgically induced menopause may have varying effects on the frequency and severity of headaches. In some studies, migraines tended to improve after physiologic menopause but not after surgical menopause. In contrast, TTH become worse or are unchanged in the majority of cases, regardless of the type of menopause.

Hormone-Replacement Therapy

Hormone-replacement therapy, consisting of one or another form of estrogen and progesterone, may exacerbate migraines that would otherwise cease. The exacerbation of migraine by HRT may occur immediately after starting treatment or gradually as a consequence of prolonged use. However, continuous administration of HRT in low daily doses may relieve persistent or new migraines. An association between current use of HRT and risk of venous thromboembolism has been identified. However, the number of reported cases is only about 1 in 5000.

Oral Contraceptives

The use of OCs, which accentuate hormonal fluctuations, is known to increase the frequency, duration, severity and complications of migraine. It should be noted that these problems are most likely to occur in women with a history of migraine. Initial onset of migraine can also occur in women who have just started using OCs. Frequently, there is a family history of migraine.

Migraine headaches are the most common adverse effect of OCs. The incidence of adverse effects, such as headache or other vascular events, has decreased over the years as newer formulations of OCs containing lower doses of estrogen have been introduced.

Treatment

Menstrual Migraine

The treatment of menstrual-related migraine may present a therapeutic challenge. Several therapies may need to be tried before reaching optimal management, and may require a combination of prophylactic agents, acute therapies and nonpharmacologic options. In general, the same agents used in acute and preventive treatment during the rest of the cycle are also efficacious perimenstrually. Like in non-menstrual migraine, nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated. This form of therapy is started 3 days prior to menses and continued through the menstrual flow. This treatment is helpful to decrease both the frequency and severity of migraine attacks. It is also helpful in treating the dysmenorrhea experienced by many patients. If one NSAID is not effective, it is often helpful to prescribe another. The NSAIDs used in menstrual migraine include:

• Fenoprofen calcium (Nalfon)
• Naproxen sodium (Anaprox)
• Mefenamic acid (Ponstel).

Another useful approach to menstrual migraine management is the focal use of triptans. For patients who experience menstrual-related migraine of longer duration which are more challenging to treat, the first stage of treatment should be a triptan rather than a pain reliever. Some investigators have suggested that the characteristics of the ideal triptan in acute therapy of these patients would include fast onset, high efficacy, excellent tolerability profile, and low headache recurrence rate. A triptan with a longer half-life, such as frovatriptan or naratriptan, may be effective in the prophylaxis of menstrual migraine. Frovatriptan 2.5 mg, almotriptan 12.5 mg, rizatriptan 10 mg and zolmitriptan 2.5 mg have comparable efficacy with respect to pain relief at 2h, pain-free response and sustained pain absence at 48h, with frovatriptan being the most efficacious at preventing recurrence. The triptans can be safely used with other medications that may be utilized by women with menstrual migraine, including NSAIDs, oral contraceptives, analgesics and migraine prophylactic agents. The triptans have been successfully combined with the NSAIDs and acetaminophen in the early treatment of migraine attacks. There is no contraindication in patients who are using oral contraceptives.

About 24 hours prior to the expected onset of the attacks, a dose of a triptan (ie, frovatriptan 10 mg initially then 2.5 mg bid, rizatriptan 10 mg bid, zolmitriptan 2.5 mg, or sumatriptan 25 mg bid) could be started on those days when the patient is at risk for a headache. In one multicenter study, menstrual migraine patients treated 625 migraine attacks with zolmitriptan 2.5 mg-tablets and 529 with placebo. The patients were allowed to treat up to two migraine headaches per menstrual period for up to 3 months. Zolmitriptan demonstrated superior efficacy over placebo at 2-hours postdose (66% vs 33%). If the patient suffers a breakthrough headache, one of the triptans may be used as rescue therapy.

Studies have been undertaken on the prophylactic use of long-acting triptans (ie, frovatriptan 2.5 mg bid or qd or naratriptan 1 mg bid) prophylactically in menstrual migraine. Results have been promising. A study of the prophylactic use of frovatriptan for menstrual-associated migraine (MAM) was undertaken in 506 patients. Patients were treated for three perimenstrual periods (PMPs)—one with placebo, one with frovatriptan 2.5 mg daily, and one with frovatriptan 2.5 mg bid. The treatment interval started 2 days prior to the anticipated onset of the MAM and continued for 4 more days. In the 6-day treatment period with placebo, 67% of the patients experienced MAM as compared with 51% of patients on frovatriptan 2.5 mg daily and 40% of patients on frovatriptan 2.5 mg bid.

The prophylactic use of naratriptan in MAM was also evaluated in a comparison study with placebo. Patients were randomized to naratriptan 1 mg bid or placebo for 6 days. The patients were asked to start treatment 3 days before expected MAM onset and to treat four PMPs. Across four PMPs, the naratriptan group experienced fewer MAM days as compared with the placebo group (5 vs 6.5).

Intermittent preventive therapy with a triptan has been suggested for patients with menstrual migraine. The goal of this therapy is to not only diminish the occurrence of migraine attacks but to decrease the duration and intensity of any attacks. If the patient experiences breakthrough headaches, the same triptan can be employed. Any of the available triptans can be considered for the intermittent therapy of menstrual migraine.

The same type of focal therapy can be achieved with dihydroergotamine (DHE)—either parenteral or nasal spray—or another ergotamine derivative. However, if an ergot preparation is used, a triptan cannot be used as rescue therapy if the patient experiences a breakthrough headache.

Patients experiencing prolonged and disabling attacks at menses may need effective preventive therapy. This treatment may decrease the frequency and severity of their attacks and actually enhance the response to acute headache therapy.

The standard options for migraine prophylaxis – eg, topiramate, β-blockers, anti-CGRP mAbs, atogepant – may also be useful in the prophylaxis of menstrual migraine. For patients refractory to other therapies, corticosteroids such as dexamethasone dose pack or methylprednisolone dose pack may be helpful. For short-term perimenstrual prophylaxis, therapeutic options include NSAIDs/COX₂ inhibitors, triptans/DHE, hormonal therapy and magnesium. Magnesium oxide 500 mg has shown efficacy in women with menstrual migraine in reducing the number of headache days per month.

Replacement of estrogen may be indicated during those times when estrogen levels plummet prior to menses. However, it may be difficult to determine when to initiate estrogen therapy and how much to give. Hormone therapy consists of estrogens, estrogen antagonists, estrogens in combination with testosterone or progesterone, and prolactin-release inhibitors. The goal is to prevent the luteal-phase increase in estrogen and/or its subsequent drop. Agents used in the treatment of endometriosis and cyclic breast pain may be effective, and replacement of estrogen prior to menstruation has proved successful.

Percutaneous estradiol gel has achieved good results, as has the use of estradiol transdermal patches that provide stable plasma estrogen levels. At least one estradiol implant has also stabilized plasma estrogen levels. Oral contraceptives may help some patients with intractable menstrual migraine, particularly if severe dysmenorrhea is also present.

Premenstrual Syndrome Headaches

Prostaglandin inhibitors, such as aspirin and other NSAIDs, have proved remarkably helpful in PMS headaches. In severe cases, anovulation therapy that includes OCs and depo-medroxyprogesterone acetate is an option. Supplemental doses of progesterone may also be efficacious. An ergotamine combination agent may be useful, particularly in treating aspects of PMS in addition to headache. Bromocriptine, a dopamine (D₂)-receptor agonist, inhibits prolactin release. When administered during the luteal phase of the menstrual cycle in a dose of 1.5 mg to 5 mg per day, this agent may decrease headache and other PMS symptoms.

Pregnancy

The treatment of headache during pregnancy imposes significant problems in selecting appropriate agents. Older retrospective studies suggested that pregnancy was often associated with remission of migraine attacks. However, that may not be true for every patient, and in fact, on a clinical basis, it is clear that patients with frequent and poorly controlled attacks may not improve during pregnancy. Given the degree of disability that migraine causes, a patient cannot tolerate a 9-month “drug holiday.”

During a patient’s pregnancy, strategies for good health should be recommended, including:

• Eating properly
• Maintaining a regular sleep schedule
• Regular exercise.

If a patient advises that she plans to become pregnant, initiating biofeedback training may be useful. These self-regulation techniques may help the pregnant patient who has stopped all drug therapy. Despite the gains achieved with biofeedback, in some patients headaches continue to be a problem.

Ergotamine preparations are contraindicated in pregnancy due to their oxytocic effects. Pain-relief measures are limited; NSAIDs (including aspirin) should be avoided due to their gastrointestinal effects and possible bleeding problems. For the acute treatment of attacks, simple over-the-counter analgesics such as acetaminophen can be used in limited quantities. For more severe attacks, transnasal butorphanol can be used as a rescue medication. Other agents, such as antihistamines and phenothiazines, are well-tolerated by the fetus and the mother. Treatment of severe attacks is important to prevent dehydration in the mother that obviously would have a significant negative impact on the infant.

The triptans are not currently recommended for use during pregnancy, although there is no data to suggest they are unsafe. A 2021 systematic review found no evidence of fetal adverse events with triptan use.

Prophylactic treatment is hampered by the potential effects on the fetus. In general, no pharmacologic prophylactic agents should be started during the first trimester. Treatment during the second and third trimesters should only be undertaken in consultation with the patient’s obstetrician. The use of the tricyclic antidepressants or fluoxetine is limited to those patients who clearly require pharmacologic intervention for psychiatric indications, particularly endogenous depression of sudden onset. When maternal depression is not optimally controlled, there is evidence of adverse effects—including neurodevelopmental—in the offspring. Other prophylactic agents, such as propranolol, may be considered. Monoclonal antibodies (mAbs) against CGRP and its receptor can cross the placenta and are currently not recommended during pregnancy.

Lactation

If a patient needs to be medicated for an acute migraine attack while breast-feeding, the triptans in general have a very short half-life. The other option is to pump and discard one or two feedings, depending on the half-life of the drug. The infant can receive stored breast milk supplemented with formula. Some prophylactic drugs are not a risk to the infant.

Menopause

In some studies in menopausal women, migraine attacks were helped by continuous use of oral or transdermal estrogen in an attempt to maintain stable serum estradiol levels. This can also be accomplished by administering depo-estradiol cypionate 5 mg intramuscularly every 2 weeks. Hormone replacement therapy is not only advocated for the relief of menopausal symptoms, but also for the prevention of osteoporosis. The lowest possible dose of estrogen should be used on an uninterrupted basis in patients with a prior history of migraine. Another form of estrogen can be utilized if the patient should encounter any problems. The risk of complications increases with the use of conjugate estrogens and ethinyl estradiol.

Many gynecologists are concerned about the increased risk of uterine cancer with the use of estrogens without added progesterone, and these physicians are also concerned about those patients who do not use cyclic estrogen therapy. The risk of endometrial carcinoma is reduced by the use of progesterone therapy for 12 to 14 days per month. Other data also suggest that long-term estrogen/progesterone combinations may increase the risk of breast cancer. It is difficult for patients to make decisions regarding HRT, but they should be encouraged to be proactive in the decision-making process about HRT. Low-dose estrogen, occasionally combined with testosterone, may be effective in those women not using HRT but who experience persistent or recent-onset migraine. Estrogen-selective receptor agents (eg, naloxone) may not trigger headache or increase the risk of breast cancer. The use of transdermal estradiol in postmenopausal women with migraine may be more effective than using oral estrogen preparations because the former type provides a more even distribution of estradiol levels.

Oral Contraceptives

Low-dose estrogen or progestin-only OCs are much better tolerated in women with migraine. Patients should be cautioned about the small increased risk of cardiovascular events, including stroke and thromboembolism. Patients should be educated about cardiovascular risk factors, especially smoking. In particular, patients with migraine with aura should be encouraged to report changes in the auras and/or migraine frequency while on OCs.

The triphasic OCs vary the estrogen dose weekly and appear to be the least tolerated of the OCs in migraine sufferers. For patients experiencing severe MAMs during the week of placebo pills, several options are available. For example, NSAIDs or focal triptans may work. One study utilized extended-duration combined oral contraceptives which were comprised of 3 months of active hormone followed by a placebo week. This form of OC pills may decrease the frequency of migraine attacks since the patient only experiences one placebo week every 3 months. Consecutive pill packs are well tolerated, although some patients complain of bloating or breast enlargement. Another option is to use an oral estrogen tablet or a transdermal patch, but it is far easier to simply continue the OC packs.