Abstract
BackgroundNeurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone sulfate, pregnanolone and estradiol in women with menstrually-related migraine and controls and analysed if a correlation existed between the levels of the three hormones and history of migraine and age.MethodsThirty women (mean age ± SD: 33.5 ± 7.1) with menstrually-related migraine (MM group) and 30 aged- matched controls (mean age ± SD: 30.9 ± 7.9) participated in the exploratory study. Pregnenolone sulfate and pregnanolone serum levels were analysed by liquid chromatography-tandem mass spectrometry, while estradiol levels by enzyme-linked immunosorbent assay.ResultsSerum levels of pregnenolone sulfate and pregnanolone were significantly lower in the MM group than in controls (pregnenolone sulfate: P = 0.0328; pregnanolone: P = 0.0271, Student’s t-test), while estradiol levels were similar. In MM group, pregnenolone sulfate serum levels were negatively correlated with history of migraine (R2 = 0.1369; P = 0.0482) and age (R2 = 0.2826, P = 0.0025) while pregnenolone sulfate levels were not age-related in the control group (R2 = 0.04436, P = 0.4337, linear regression analysis).ConclusionLow levels of both pregnanolone, a positive allosteric modulator of the GABAA receptor, and pregnenolone sulfate, a positive allosteric modulator of the NMDA receptor, involved in memory and learning, could contribute either to headache pain or the cognitive dysfunctions reported in migraine patients. Overall, our results agree with the hypothesis that migraine is a disorder associated with a loss of neurohormonal integrity, thus supporting the therapeutic potential of restoring low neurosteroid levels in migraine treatment.
Highlights
Altered levels of neurosteroids, by changing the balance between neuroexcitation and neuroinhibition in the central nervous system (CNS), can affect psychiatric and neurological disorders [1]
We found lower levels of allopregnanolone, a positive allosteric modulator of the γaminobutyric acid type A (GABAA) receptor, in women with menstrually-related migraine than in controls
We found no differences in progesterone levels between women with menstrually-related migraine and non-headache women, but we did not measure estradiol or pregnanolone, an isomer of allopregnanolone, an agonist of the GABAA receptor [3]
Summary
By changing the balance between neuroexcitation and neuroinhibition in the central nervous system (CNS), can affect psychiatric and neurological disorders [1]. We found lower levels of allopregnanolone, a positive allosteric modulator of the γaminobutyric acid type A (GABAA) receptor, in women with menstrually-related migraine than in controls. These data suggested that the reduced levels of allopregnanolone, an inhibitory neurosteroid, were insufficient to counteract the neuronal hyperexcitability associated with migraine [2], contributing to the severity of menstrual related migraine attacks [3]. It would be important to study neuroactive steroids with excitatory functions such as pregnenolone sulfate (pregn-5-en-3β-ol20-one 3β-sulfate) This neurosteroid acts as a positive allosteric N-methyl-D-aspartate (NMDA) receptor modulator [6, 7] and is a potent stimulator of transient receptor potential melastatin-3 (TRPM3) channels, that function as nociceptors in the somatosensory system [8]. We compared the serum levels of pregnenolone sulfate, pregnanolone and estradiol in women with menstrually-related migraine and controls and analysed if a correlation existed between the levels of the three hormones and history of migraine and age
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