Effect of sodium valproate on the secretion of prolactin, cortisol and growth hormone in migraine patients

A single oral dose of 500 mg sodium valproate had no effect on prolactin, growth hormone and cortisol secretion in 10 migraine patients when compared with five healthy controls and four migraine patients receiving placebo. Basal values of prolactin (PRL), cortisol and growth hormone (GH) were within the normal range, though PRL basal levels were lower in three patients (21.5%) in the migraine group.     

Ovarian steroid levels in migraine with and without aura

Radioimmunoassays were used to measure interictal levels of ovarian steroids (oestradiol, total oestrogens and progesterone) in migraine patients at the onset of menses and coincident with the luteinizing hormone surge preceding ovulation. Results of these verified biochemically-contrasting points of the ovarian cycle were used to compare 13 migraine patients without aura and 6 migraine patients with aura with 17 non-migraine women. No group differences were found for physiological basal levels of ovarian steroids measured at menses. Preceding ovulation elevation in oestradiol levels relative to normal was found in migraine patients with aura but not in migraine patients without aura. These results suggest that a variation in oestradiol levels is an important factor in the different clinical expressions of migraine.     

Possible involvement of dopaminergic mechanisms in the antimigraine action of flunarizine

Flunarizine, a calcium antagonist widely used in the prophylactic treatment of migraine, may interfere with dopaminergic systems. Flunarizine therapy can in fact induce extrapyramidal side effects and can increase basal as well as stimulated prolactin levels. To better define the mechanism of flunarizine action in migraine, we studied prolactin and growth hormone responses to thyrotropin releasing hormone and sulpiride in 13 female migraineurs before and after 60 days of flunarizine therapy. The treatment did not modify basal prolactin and growth hormone levels, but prolactin response to thyrotropin releasing hormone was enhanced. A paradoxical increase of growth hormone to thyrotropin releasing hormone observed before therapy was blunted after flunarizine treatment. These data indicate a modulatory action of flunarizine on dopaminergic systems which might to some extent explain the antimigraine action of this drug.     

1-Deprenyl test in migraine: neuroendocrinological aspects

We evaluated the effect of 1-deprenyl, a drug that increases the availability of endogenous dopamine, on the plasma levels of prolactin and growth hormone in 10 female patients with migraine and in 10 control subjects matched for age and menstrual phase. The patients showed a significant decrease in prolactin levels at 30, 60 and 120 min after the oral administration of 5 mg of 1-deprenyl when compared with the values obtained in controls ( p < 0.001). The effects of 1-deprenyl on growth hormone plasma levels were not significantly different between patients and controls. These data suggest that 1-deprenyl inhibits prolactin release in migraine patients, but not in control subjects. This differential sensitivity could be explained by dopamine receptor supersensitivity in migraine patients.     

Luteal phase ovarian steroids,stress arousal,premenses perceived stress,and premenstrual symptoms

The purpose of this study was to examine the relationships among perceived stress, ovarian steroids (estradiol and pregnanediol), stress arousal indicators (cortisol, catecholamines) and premenstrual symptoms (turmoil, fluid retention). Women (N = 74) with low symptom severity (LS), premenstrual syndrome (PMS), or premenstrual magnification (PMM) symptom patterns provided daily urine samples over one cycle and recorded their symptoms and perceived stress levels in a health diary. Multiple regression analysis was used to test models of premenstrual symptoms in separate analyses for women with the LS and PMS symptom patterns and the LS and PMM symptom patterns. Data from the LS and PMS groups revealed that greater stress ratings accounted for turmoil symptoms and higher luteal phase cortisol levels for fluid retention symptoms. For LS and PMM groups, lower luteal phase norepinephrine levels, higher global stress ratings, and a more gradual drop in estradiol premenses accounted for turmoil symptoms. Premenses norepinephrine and epinephrine levels and premenses stress ratings accounted for fluid retention. These findings support an important relationship among perceived stress, stress arousal indicators, and premenstrual symptoms that differs for women with a PMS and PMM symptom pattern. © 1998 John Wiley & Sons, Inc. Res Nurs Health 21: 129–142, 1998     

Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone in common migraine

Intravenous administration of 50 micrograms or 200 micrograms thyrotropin-releasing hormone (TRH) to men with common migraine elicited blunted prolactin (PRL) responses, when compared with healthy controls. The thyroid-stimulating hormone (TSH) response was enhanced after 50 micrograms TRH in the migraineurs, but not after 200 micrograms. The physiologic TSH dose-response relationship was abolished in migraine sufferers. The data may be interpreted in the light of dopaminergic and noradrenergic supersensitivity, for PRL and TSH, respectively. The TSH response in migraine differs from the one that occurs in depression.     

Steroids and aseptic osteonecrosis (AON) in migraine patients

Osteonecrosis is a bony infarction caused by disruption of blood supply to the bone. Aseptic osteonecrosis should be rare with intermittent use of steroids in disabling and refractory migraine cases. We present 3 cases of patients who had severe migraine and developed aseptic osteonecrosis with short-term, intermittent pulse doses of corticosteroids. Migraine has been mentioned as a possible risk factor for aseptic osteonecrosis, and we speculate that severe migraine may be a risk factor for developing aseptic osteonecrosis. Furthermore, migraineurs who develop aseptic osteonecrosis may or may not have associated white matter changes in the brain. We noted a triad of severe migraine, osteonecrosis, and migraine-related white matter lesions in only 1 case. In severe cases of migraine, steroids should be used cautiously.     

Prolactin in cluster headache: Diurnal secretion, response to thyrotropin-releasing hormone, and relation to sex steroids and gonadotropins

The diurnal rhythmicity of serum prolactin (PRL) and the PRL and thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) were studied in 31 cluster headache patients (4 chronic cases) and 14 healthy controls. Sixteen of the patients were studied both during clinical remission and headache periods. In males the nocturnal PRL peak was blunted during remissions as compared with that in cluster periods and that in control individuals. The 24-h mean PRL levels were lower during remission and cluster periods than in the controls. There were no significant differences in the PRL levels between female patients and controls. Headache attacks were often associated with increases of serum PRL levels. The PRL reponse to TRH was lower in the female patients but not in the male patients as compared with controls. The maximum testosterone levels were lower during cluster periods than during clinical remission but not when compared with controls. Serum levels of luteinizing hormone, follicle-stimulating hormone, progesterone, estradiol, T₃, T₄, and TSH did not differ between patients and controls. The results suggest an altered regulation of PRL secretion not only during active cluster periods but also during symptom-free intervals. The possible influence of sleep, estradiol, testosterone, medication, pain, and serotoninergic and dopaminergic mechanisms are discussed.     

Urinary 5-HIAA in migraine: Evidence of lowered excretion in young adult females

Urinary 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in 44 young adult migraine patients (35 women, 9 men) between attacks and in 33 healthy controls (23 women, 10 men). HVA excretion was equivalent in all groups. 5-HIAA was unaltered in men but was significantly decreased in female migraine patients when compared with their sex-matched controls (-31%, p less than 0.01). No relationship was found between 5-HIAA excretion and the various characteristics of migraine, such as the time that had elapsed since the last attack and the presence or absence of oral contraception. The relatively marked decrease in 5-HIAA excretion in female migraine patients can hardly be accounted for by a reduction in either neuronal or platelet serotonin metabolism alone. A reduction in the intestinal contribution to urinary 5-HIAA might be the crucial factor.     

Melatonin secretion is supersensitive to light in migraine

The present study examined the sensitivity to light of melatonin (MLT) secretion in familial migraine during a headache-free interval. Twelve female patients and 12 healthy controls were included in the trial. All subjects were studied twice. In each session, light exposure (300 lx) or placebo was randomly administered for 30 min between 00.30 and 01.00 h. Blood was sampled hourly between 20.00 and 24.00 h, and 02.00 and 04.00 h and every 15 min between 00.30 and 01.30 h. Plasma MLT levels were determined by radioimmunoassay. MLT suppression was more marked in the migraine group than in the control group [difference of area under curve (DeltaAUC)=-53.8 +/- 16.2 vs. 18.5 +/- 12.7 pg/h/ml, P<0.005; maximum of MLT suppression (Delta)=-35.7 +/- 10.2 vs. - 6.7 +/- 5.8 pg/ml, P<0.05]. These findings show a clear hypersensitivity to light in young female migraineurs during the headache-free period.     

Triptans in the treatment of basilar migraine and migraine with prolonged aura

OBJECTIVE: To report on the use of triptans in migraine with prominent neurologic symptoms. BACKGROUND: As stated in their package inserts, the triptans are contraindicated in patients with basilar or familial hemiplegic migraine, and physicians are reluctant to prescribe these drugs to other patients with prominent or prolonged aura. METHODS: We evaluated 13 patients with basilar migraine, familial hemiplegic migraine, or migraine with prominent or prolonged aura who had received triptans. RESULTS: Excellent; no adverse events. CONCLUSION: The contraindication of triptans in basilar migraine should be reconsidered. Similarly, prominent or prolonged aura may not represent a reasonable contraindication to triptan therapy.     

Dopamine and migraine: a review of pharmacological, biochemical, neurophysiological, and therapeutic data

The dopamine theory of migraine pathogenesis, first proposed by F. Sicuteri in 1977, has attracted renewed interest after an increased frequency of the dopamine D2 receptor (DRD2) gene allele Nco I C was found in patients with migraine with aura. Therefore we reviewed the relevant literature. The most compelling argument favoring an interictal hypersensitivity of dopamine receptors in migraineurs stems from pharmacologic studies of the gastric and autonomic effects of dopaminergic agents such as apomorphine, but none of these studies was blinded and placebo-controlled. Various DRD2 antagonists abort migraine attacks after parenteral administration, while there is circumstantial evidence that dopamine agonists may be useful for prophylaxis. Most drugs used in these trials, however, lack selectivity for dopamine receptors. Both in pharmacological and therapeutic studies most patients had migraine without aura. We conclude that data suggesting a primary role for the dopaminergic system in migraine pathogenesis are unconvincing. Based on well established interactions between central amines, a reduced release of serotonin between attacks could lower dopamine release which would lead to receptor hvpersensitivity.     

Changes in the 24-hour prolactin pattern in cluster headache

The regulation of prolactin (PRL) secretion periodicity in cluster headache (CH) and in atypical facial pain (AFP) has been studied in nine and seven patients, respectively. The physiological periodicity of the hormone secretion, with its highest levels during night sleep and its lowest during the waking hours, is upset in CH, but not in AFP. A rhythmicity occurs in CH only in the presence of severe pain, which appears to be the synchronizing event. Lithium carbonate treatment does not interfere with the mentioned changes in PRL secretion in CH.     

Changes in platelet membrane fluidity of migraine patients

Platelet membrane fluidity was measured in migraine patients, with and without aura, using the fluorescent probe TMA-DPH (1-[4-(trimethylammonium) phenyl]-6-hexa-1,3,5-triene). Polarization values for TMA-DPH were significantly higher in the platelet membranes of migraine patients (with or without aura) than in those of healthy subjects. These findings signify decreased membrane fluidity and may explain some modifications in receptors, carriers or enzymes described in platelets of migraine patients.     

Changes in cortical processing of pain in chronic migraine

OBJECTIVE: The aim of this study was to perform a topographic and dipolar analysis of nociceptive-evoked responses obtained by laser stimulus under basal conditions in a cohort of chronic migraine (CM) patients, compared with migraine without aura (MWA) patients and noncraniofacial pain controls. BACKGROUND: An increased activation of cortical areas devoted to the emotional and attentive components of pain was previously found during the course of the migraine attack; it was more pronounced in patients reporting higher frequency of migraine. METHODS: Twenty-six outpatients were enrolled in the study; 16 fulfilled the criteria of CM, and 10 were affected by MWA. Fifteen noncraniofacial pain subjects were also selected. The pain stimulus was a CO2 laser pulses. The right-supraorbital zone was stimulated. Source localization analysis was performed on the most prominent laser-evoked potentials (LEPs) peak (P2) for each data set. The anatomical locations of the P2 sources were projected onto a standard normalized 3D MRI model. RESULTS: The CM group differed significantly from both MWA patients and controls for the x coordinate and from controls for the z coordinates. The P2 dipole localized in the rostral cingulate cortex in CM patients, lying in a more posterior location within the anterior cingulate cortex (ACC) in both controls and MWA patients. The x coordinate of the P2 dipole, expressing the postero-anterior location, was significantly correlated with frequency of headache. CONCLUSIONS: CM seems to be characterized by a distinctive pattern of cortical elaboration of pain, with a prevalent activation of the rostral portion of the ACC: our results suggest that this may be a predisposing factor to migraine chronicity.     

Defective dopaminergic regulation of prolactin secretion in patients with hyperprolactinemia

In order to evaluate the dopaminergic control of the lactotroph, we examined the plasma prolactin response to metoclopramide (a dopamine receptor blocker, 10 mg iv bolus) and to dopamine (1 microgram/Kg/min iv infusion for 120 min) in 52 hyperprolactinemic female patients and 19 healthy volunteer women. Three diagnostic categories were included: "idiopathic" hyperprolactinemia (21), microadenoma (24), and macroadenoma (7). Patients from all groups showed a marked blunting of the prolactin response to metoclopramide as compared to the prolactin rise in normal women (p less than 0.001). However, normal responses were observed in 8 patients with idiopathic hyperprolactinemia and in one patient with adenoma. The magnitude of the prolactin response to metoclopramide (percent of baseline level) correlated negatively with the level of basal prolactin in each group except for macroadenoma patients. Dopamine infusion significantly (p = 0.015) reduced the mean plasma prolactin levels in hyperprolactinemic patients and normal women. However, patients with idiopathic hyperprolactinemia were hyposensitive to dopamine (p less than 0.05). Furthermore, microadenoma patients were less responsive to dopamine suppression than were the patients with macroadenoma (p less than 0.05). The results indicate the presence of a relative resistance to dopamine in patients with idiopathic hyperprolactinemia and in patients with microadenoma. They also suggest that in these patients, the decrease in prolactin response to metoclopramide may be explained by the relative refractoriness to endogenous dopamine.     

Defining the relationship between ovarian hormones and migraine headache

OBJECTIVE: (1) To determine whether the attack characteristics of migraine differ between different intervals of the menstrual cycle; (2) To ascertain whether the "rate of change,"magnitude of change," or "total burden" of urinary hormone metabolites correlates with headaches outcome measures during different intervals of the menstrual cycle. BACKGROUND: The mechanisms through which migraines are influenced by ovarian hormones remain unclear. No previous studies until now have identified "hormonally defined" time intervals within the female menstrual cycle and compared headache outcome measures among these intervals in female migraineurs. METHOD: Daily headache diary data were obtained from 21 female migraineurs during three native menstrual cycles. Daily urine samples were collected and later assayed for estrogen and progesterone metabolites. Seven 3-day time intervals were identified within each menstrual cycle based on urine hormone measurements. Primary (headache index) and secondary (disability index, headache severity, and headache frequency) outcome measures were compared between intervals using the mixed model approach. "Rates of change,"magnitude of change," and the "total burden" of ovarian hormones were estimated from urine hormone metabolites and correlated with headache outcome measures. RESULTS: The headache index was significantly different across different intervals of the menstrual cycle (P values <.001) and was higher during menstrual intervals (first 6 days of the menstrual cycle) than during mid-cycle and mid-luteal intervals (P < .002). Similarly, secondary outcome measures were highest during the menstrual intervals. "Higher burdens" of urinary progesterone metabolites were positively correlated with headache outcome measures during the luteal intervals of the menstrual cycle. "Rates of change" and the "magnitude of change" of urinary hormone metabolites did not correlate with headache outcome measures. CONCLUSIONS: Migraine headache is more severe, disabling, and frequent during the menstrual intervals of the female reproductive cycle than during mid-luteal or mid-cycle intervals. Progesterone metabolites may play a role in modulating migraine headaches during luteal intervals of the menstrual cycle.     

Changes of neuroendocrine axes in patients with menstrual migraine

Menstrual migraine (MM) is a menstrually related disorder (MRD) characterized by several symptoms in common with premenstrual syndrome (PMS). It has been hypothesized that in both MM and PMS hormonal cyclicity could change the balance of neurotransmitters and neuromodulators like monoamine and opioid. In this article we analyze all the data collected by our group on the central opioid tonus and the adrenergic and serotonergic systems in patients affected by menstrual migraine.