Opioid control of the hypothalamus-pituitary-adrenal axis cyclically fails in menstrual migraine

To assess the biological correlates of the precipitation of migraine attacks in the perimenstrual period, plasma β-endorphin (β-EP) and cortisol responses to naloxone (8 mg iv) and corticotropin releasing hormone (100 μg iv) were evaluated in both the follicular phase and the premenstrual period in 7 patients suffering from menstrual migraine and in 7 healthy, asymptomatic control volunteers. In the controls, naloxone evoked a significant release of both β-EP (F = 5.86, p <0.002) and cortisol (F = 4.43, p <0.008), independently of the menstrual cycle phase (F = 0.31 and 1.04, for β-EP and cortisol, respectively). Menstrual migraine patients, on the other hand, showed a significant hormone response only in the follicular phase, not in the premenstrual period. Corticotropin releasing hormone significantly increased β-EP and cortisol in both the controls and the menstrual migraine patients, independently of the menstrual cycle phase. In both the naloxone and corticotropin releasing hormone testings, the basal β-EP levels measured in the premenstrual period were lower than those observed in the follicular phase (p <0.02). These data demonstrate a cyclical, premenstrual dysfunction of the hypothalamic control exerted by opioids on the hypothalamus-pituitary-adrenal axis. Impairment of this fundamental adaptive mechanism (involved in stress responses and in pain control) could establish a causal relationship between menstrual-related migraine attacks and premenstrual opioid hyposensitivity.