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Migraine Headache

What Causes Migraine?

In the early years of migraine research, scientists believed that the headache portion of a migraine resulted from the dilation of blood vessels, while the aura portion of migraine was caused by vasoconstriction (Cutrer 2012). However, more recent evidence suggests that these vascular changes are not the cause of migraine, but rather an epiphenomenon that accompanies the pain (Rizzoli 2012). Today, migraine is viewed as a result of complex dysfunction within the central nervous system (Charles 2009). Various factors that contribute to this dysfunction are reviewed below.


The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) plays a role in the development of migraine attacks. This conclusion is supported by evidence indicating that migraine patients tend to have low levels of serotonin in their brains (Panconesi 2008). Additional support for this theory is found in data indicating that tricyclic antidepressants, which increase serotonin signaling, reduce the frequency of migraine attacks (Cutrer 2012).

Furthermore, melatonin, an active metabolite of serotonin (Gyermek 1996), has also been found to be deficient among migraine patients (Masruha 2008; Masruha 2010), and melatonin supplementation has resulted in symptom improvement among some migraine patients (Vogler 2006).

Although the exact mechanism linking low serotonin levels to migraine pathology has not yet been fully described (Hamel 2007), researchers have hypothesized that serotonin may interfere with pain processing in the brain. Serotonin also affects on the dilation and contraction of blood vessels in the brain (Cutrer 2012).

Though low serotonin levels may give rise to an attack, some evidence suggests that elevated serotonin levels may contribute to migraine pathology during an attack (Sakai 2008; Chugani 1999). Due to the complexity of serotonin's role in migraine, further study is needed to fully characterize the effects of modulating serotonin levels and/or signaling in migraine patients.

The Role of Hormones

Migraine disproportionately affects women – females make up about 70% of all migraine patients – suggesting a potential hormonal link (Dhillon 2011).

Although many hormonal events in a female's life may influence the occurrence of migraine (e.g., menarche, menstruation, pregnancy, and menopause) (Sacco 2012), menstruation appears to be the most important. For example, 70% of female patients who experience migraine report some type of menstrual link (Calhoun 2012). A phenomenon called "estrogen withdrawal," which occurs in the late luteal phase of the menstrual cycle and is characterized by an abrupt decline in estrogen levels, is likely an important migraine trigger in some women (MacGregor 2009, Lay 2009).

Fluctuations in estrogens levels associated with migraine produce biochemical changes in prostaglandin production, prolactin release, and endogenous opioid regulation (Dzugan 2004, 2006).

Prostaglandin E2 (PGE-2) is a well-defined mediator of fever and inflammation. PGE-2 increases vasodilatation and thereby induces pain. Estrogens increase the production of PGE-2. An excess of estrogens, deficit of progesterone, or dominance of estrogens can cause increased production of PGE-2, resulting in migraine.

Elevation of the prolactin level or increased sensitivity to prolactin leads to a decreased level of prostaglandin E1 (PGE-1). Patients with migraine may have prostaglandin-induced hyper-sensitivity to prolactin. PGE-1 is a substance that in fact improves the microcirculation and leads to the development of collateral circuits with a consequent improvement in local hemodynamics.

If a patient has a dominance of PGE-2, vasodilatation of major arteries with spasm of collateral circuits would be expected, which in turn can cause pain. Restoration of hormonal levels and balance between them can stabilize levels of prostaglandins.

Steroid hormones also influence the metabolism of calcium and magnesium. Estrogens regulate calcium metabolism, intestinal calcium absorption, and parathyroid gene expression and secretion, triggering fluctuations across the menstrual cycle. Alterations in calcium homeostasis have long been associated with many affective disturbances.

Clinical trials in women with premenstrual syndrome have found that calcium supplementation may help alleviate most mood and somatic symptoms. Evidence to date indicates that women with symptoms of premenstrual syndrome have an underlying calcium abnormality (Thys-Jacobs 2000). A low brain magnesium level can be an expression of neuronal hyperexcitability of the visual pathways and be associated with a lowered threshold for migraine attacks (Aloisi 1997). Clinically, it is known that magnesium supplementation relieves premenstrual problems (for example, migraine, bloating, and edema) that occur late in the menstrual cycle, and that migraine, particularly in women, is associated with deficiencies in brain and serum magnesium levels. Testosterone was not shown to produce any significant alteration in magnesium levels, but estrogens and progesterone do (Li 2001).

Among women with menstrual-related migraines, using hormone therapy to minimize monthly declines in estrogen concentration may be effective in preventing migraine attacks (Calhoun 2009). Studies suggest that non-oral routes of estrogen therapy, such as a topical cream to be applied to the skin, are more likely to improve migraine than oral estrogens (MacGregor 2009).

More information about hormone testing and restoration is available in the Female Hormone Restoration protocol.

The Neurohormonal and Metabolic Dysbalance Hypothesis of Migraine

Some researchers suspect that an important cause of migraine is an imbalance between estrogens and progesterone levels, rather than the absolute levels of these hormones. Indeed, therapies aimed at improving the ratio of estrogens to progesterone have successfully relieved severe menstrual migraine in preliminary reports (Holdaway 1991).

Some innovative physicians believe that consideration should be given to the balance of other sex hormones as well, including testosterone, dehydroepiandrosterone (DHEA), and pregnenolone (Dzugan 2006).

According to the Neurohormonal and Metabolic Dysbalance Hypothesis of Migraine, migraine is not a single disorder, but a collection of disorders involving faulty hormonal feedback in the hypothalamic-pituitary-adrenal-gonadal axis.

Contributing to this hormonal abnormality is an imbalance between two of the three arms of the autonomic nervous system (the sympathetic and parasympathetic nervous systems), which causes a decline in the brain's pain threshold. Because of disequilibrium between intra- and extracellular calcium and magnesium, the polarity of the cell membrane is changed, which affects the electrical stability of the cell membrane and sensitivity to neurohormonal impulses (steroid hormones, melatonin, and serotonin).

Although well-controlled clinical trials designed to test the hypothesis that comprehensive hormone testing and balancing may relieve migraine headaches are lacking, several case reports present positive outcomes using this novel approach (Dzugan 2006).

One link between hormonal imbalance and migraine may stem from the opposing roles of estrogen and progesterone within the brain. While estrogen stimulates neural excitability, progesterone exhibits inhibitory actions in central neurons (Finocchi 2011). Therefore, imbalance between these neuromodulatory hormones may give rise to physiological conditions that alter susceptibility to migraine (Finocchi 2011).

Tailored hormonal replacement therapy (HRT) aimed at minimizing estrogen/progesterone imbalance and stabilizing estrogen levels may be effective for preventing migraines among pre- and post-menopausal women (Nappi 2009; Shuster 2011; Schurks 2010; Calhoun 2012). In the words of some forward thinking migraine researchers - "clinical experience strongly supports the notion that migraine can be managed only when levels of all the basic hormones—pregnenolone, DHEA, testosterone, estrogen, and progesterone—are optimal with the physiological cycle" (Dzugan 2003).

Women suffering migraines without relief through conventional medical treatments should consider comprehensive hormone testing and restoration of hormonal balance using bioidentical hormone replacement therapy.