In nine women suffering from menstrual migraine (MM), and in six healthy asymptomatic volunteers, plasma beta-endorphin (beta-EP), growth hormone (GH), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) concentrations were measured in response to clonidine (0.075 mg, i.v.) stimulation. In MM patients clonidine testing was performed in both the early and the late luteal phases of the menstrual cycle. Premenstrual symptoms were prospectively evaluated in the actual cycle using the Moos Menstrual Distress Questionnaire. beta-EP (after gel chromatography) and GH were measured using radioimmunoassay. NE and MHPG were evaluated by HPLC using electrochemical detection. In both phases of the menstrual cycle clonidine significantly reduced NE and MHPG levels in MM patients and controls in a similar way. In MM patients beta-EP and GH plasma levels were stimulated by clonidine only in the early luteal phase, whereas they remained unchanged when they were stimulated in the premenstrual period. In controls the response of both hormones was not affected by the menstrual cycle. The lack of hormonal response to clonidine in MM may suggest a postsynaptic alpha 2-adrenoreceptor hyposensitivity during the premenstrual period. This demonstrates a transient vulnerability of the neuroendocrine/neurovegetative systems, and could thus be a factor facilitating the precipitation of both behavioral changes and migraine attacks.