An Innovative New Treatment for MigraineSeptember 2004
By Dr. Sergey A. Dzugan
Sex Hormones and Headaches
Migraine affects approximately three times as many women as men, suggesting that gonadal steroids may play a role. Furthermore, headaches have been linked to menstrual cyclicity. Migraine attacks occur during menses in 60% of women. Changes in estrogens levels at menarche and during menstruation, pregnancy, and menopause may trigger migraine. Indeed, the physiological decline in estrogens levels that occurs with menstruation, or a therapeutic withdrawal as occurs during hormonal blocking therapy, often precipitates migraine, whereas the sustained high estrogens levels that occur during pregnancy frequently result in relief from headaches.51,52
In some cases, estrogens replacement therapy for menopausal symptoms induces headache. The incidence and severity of migraine are also affected by use of oral contraceptives.53 In migrainous women, 17-beta-estradiol levels are higher in both the follicular (before release of an egg) and luteal (after release of an egg) phases of the menstrual cycle, whereas progesterone concentrations and the ratio of progesterone to estradiol are lower than in healthy subjects during the luteal phase of the menstrual cycle.54 Menstrual distress was highest during the luteal and menstrual phases of the cycle, and these symptoms were related to higher estradiol levels, higher ratios of estradiol to progesterone, and increased headache activity.55
Because of these controversies, we maintain that the main problem is an imbalance between estrogens and progesterone levels rather than the absolute levels of these hormones. This can explain, for example, why migraine was relieved by using Zoladex®, which blocks estrogen release from the ovary and improves the ratio of estrogens to progesterone.56 Menstrual migraine therefore represents a model that coincides with a neuroendocrine hypothesis.13 Effects of hormonal imbalances and deficiencies on vasomotor control are clinically significant, and hormonal treatment is often effective in managing various conditions caused by abnormal blood flow, including migraine.57
In this way, estrogens are known to exert their influence by modulating sympathetic control of cerebral vasculature.12 Not surprisingly, various trials have been conducted using estrogens, progestogens, and dehydroepiandrosterone (DHEA) to manage migraine; the findings from these trials, however, have been inconsistent.58-60 Despite copious research, the proper therapeutic use of hormones remains in question.61,62
The fluctuations in estrogens levels associated with migraine also produce biochemical changes in prostaglandin production, prolactin release, and endogenous opioid regulation. 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 the patient has a dominance of PGE-2, we would expect vasodilatation of major arteries with spasm of collateral circuits, 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.63 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.64 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.65
In some but not all studies, patients with migraine showed a significant reduction of testosterone and a significantly increased cortisol concentration.66-69 We believe that a normal level of testosterone does not necessarily equate with an optimal level. Little attention has been paid thus far to androgens and their role, if any, in causing migraine.70,71 Our 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.72
A New Hypothesis
The findings just described, in conjunction with our clinical observations, have led us to hypothesize that migraine is a specific consequence of the imbalance between neurohormonal and metabolic integrity. Based on our clinical experience, we have therefore suggested a unifying hypothesis, which we call the Neurohormonal and Metabolic Dysbalance Hypothesis of Migraine. Such a hypothesis not only brings together the many seemingly disconnected research findings for the first time, but also provides guidance for an effective treatment approach.
Migraine is not a single disorder, but a collection of disorders. According to our hypothesis, a migraine involves 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). Lastly, the intestinal flora is altered, which results in abnormal absorption.
The Migraine Solution
The old approach of focusing on the treatment of symptoms was replaced in our study with treating the cause of the disease. Herein we present our clinical experience with a series of particularly difficult-to-treat migraineurs in whom we simultaneously restored neurohormonal and metabolic integrity. We offered our treatment to 23 patients (21 women and 2 men) from May 2001 to May 2004. The patients ranged in age from 29 to 66, with a mean age of 46.7. The main characteristics and clinical summaries of these patients before treatment are reported in Table 1 on the following page.
All of our patients had attempted—without success—to prevent or treat migraine with up to four standard drugs for periods ranging from 2 to 36 years (with a mean of 16.7 years). Nearly three of four patients (73.9%) had used hormone replacement therapy or oral contraceptives. Concurrent illnesses were noted as follows: fatigue in 100% of patients; depression in 95.7% of patients; insomnia in 82.6% of patients; and fibromyalgia in 21.7% of patients. This was consistent with other reports.73-76 Fibromyalgia, chronic fatigue, and primary headaches are common and debilitating disorders with complex interactions among each other.77 We believe that this relationship is based on common abnormalities and that successful treatment is possible.