migraine is a kind of headache which is caused by the alterations in trigeminovascular system , but the pathophysiological mechanisms have not still been fully delineated . today , it is known that the vascular alterations are not limited to cranial vessels , and migraine is suggested to be a systemic vasculopathy . the vasculopathy of migraine is thought to reflect the endothelial dysfunction and impaired vascular reactivity . the activation of the platelets and the coagulation factors , the increased secretion of von willebrand factor and tissue plasminogen activator from endothelium , the decrease in the circulating endothelial progenitor cells , which are all seen in migraine , support this theory . the demonstration of similar c - reactive protein ( crp ) levels in migraineurs and healthy control subjects in recent studies [ 5 , 6 ] , although it had been found high in previous studies [ 79 ] , necessitates new investigations and data about this issue . the increasing number of studies in the past decade showed that the risk of cardiovascular disease is increased in migraine [ 1013 ] . elevated high - sensitivity crp ( hscrp ) , interleukin 6 and soluble cd40 ligand ( scd40l ) levels are associated with the increased risk of cardiovascular disease [ 14 , 15 ] . soluble cd40l is a ligand of glycoprotein iib - iiia receptor and is involved in thrombus stabilization and platelet activation . prolactin , secreted from anterior pituitary gland and meanwhile also synthesized by various immune system cells , has been reported to cause a tendency to the cardiovascular diseases . on the other hand , hyperprolactinemia induces migraine attacks   and also plays a role in other primary headache syndromes . it is known that dopaminergic dysfunction is responsible from autonomic symptoms such as nausea and yawning . in this study , we aimed to investigate the scd40l , prolactin and hscrp levels in migraine patients during interictal period and their relationship with migraine subtypes and attack frequency . fifty female migraine patients and age - matched 25 female control subjects were enrolled in the study . migraine diagnosis was settled according to the international classification of headache disorders - ii diagnostic criteria . twenty - three patients had migraine with aura , while the rest had migraine without aura . the control subjects were enrolled as healthy individuals who had no headache of any kind . the study was approved by the local ethics committee , and all patients gave their informed consent to participate in the study . exclusion criteria included pregnancy , disorders and drugs which affect the prolactin levels such as butyrophenones , phenothyozines , reserpine or methyldopa , history of prolactinoma , hypothyroidism , chronic renal failure and cirrhosis . a questionnaire was completed about the existence of vascular risk factors such as hypertension , diabetes , smoking and family history of cardiovascular diseases . body mass index ( bmi ) was calculated on the basis of world health organization ( who ) recommendations . serum samples were collected from an antecubital vein without using a tourniquet , between 08:30 and 09:00  a.m. after overnight fasting . for hscrp , scd40l and prolactin , venous blood samples were centrifuged within 15  min at 3,000  rpm for 10  min , and the supernatant serum samples were transferred into polypropylene tubes at 80c until the assays were performed . soluble cd40l and hscrp levels were measured by elisa ( biosource , immunoassay - kit , usa ; drg inc . , usa , respectively ) and prolactin levels by chemiluminesense immunoassay ( dpc , immulite 2000 , usa ) . the participants serum fasting glucose levels were measured using the glucose oxidase technique ( konelab 60 , finland ) . cholesterol esterase enzymatic assays ( konelab 60 , finland ) were used to measure total cholesterol and high - density lipoprotein - cholesterol ( hdl - c ) . low - density lipoprotein - cholesterol ( ldl - c ) levels were calculated according to friedewald s formula . values of the platelet count and mean platelet volume were obtained from whole blood count analysis . student s t test and pearson correlation analyses were used for normally distributed variables . the mann whitney u test and spearman rank correlation test were used for non - parametric variables . the characteristics of the migraine patients and the control subjects are shown in table  1 . age , anthropometric values , blood pressure , serum fasting glucose and lipid levels did not differ between the two groups . no difference was found between the prolactin levels of the migraine patients and the controls . the scd40l levels were significantly higher in migraine patients ( p  <  0.001 ) . there was no correlation between the prolactin , scd40l and hs - crp levels in migraine patients ( p  >  0.05 , for all ) . soluble cd40l remained significantly high in the migraine group after adjusting for bmi of both the groups ( p  =  0.002 ) . mean platelet volume of migraine patients was significantly higher than that of the control group ( p  <  0.05 ) and was correlated with scd40l levels ( r  =  0.362 , p  <  0.05).table  1the clinical and laboratory characteristics of all participantsmigraine subjects ( n  =  50)control subjects ( n  =  25)page ( years)38.0    8.634.4    7.8nshypertension ( % ) 9.39.0nsdiabetes mellitus ( % ) 4.40nssmoking ( % ) 42.450nsbmi ( kg / m)26.54    5.5223.98    3.18<0.05systolic bp ( mmhg)118.09    17.4123.63    23.77nsdiastolic bp ( mmhg)77.44    16.3477.27    11.03nsglucose ( mg / dl)91.76 10.7693.85    22.8nscholesterol ( mg / dl)189.88    38.04183.42    40.28nstriglyceride ( mg / dl)106.21 44.54102.85    53.97nsldl ( mg / dl)119.92    32.38111.68    32.90nshdl ( mg / dl)50.03    12.5249.29    15.88nsplatelet ( /mm)274361    59207263062    60698nsmpv ( fl)9.53    1.48.7    0.92<0.05prolactin ( ng / ml)11.34    8.6310.89    5.0nshs - crp ( mg / l)4.28    4.013.91 3.89nsscd40l ( ng / ml)11.92    5.267.72    3.6<0.001ns non - significant , bp blood pressure , mpv mean platelet volume , hscrp high - sensitivity c - reactive protein , scd40l soluble cd40 ligand the clinical and laboratory characteristics of all participants ns non - significant , bp blood pressure , mpv mean platelet volume , hscrp high - sensitivity c - reactive protein , scd40l soluble cd40 ligand no difference was found between migraine with aura and migraine without aura groups regarding the scd40l , hscrp and prolactin levels ( table  2 ) . when the migraine patients were subdivided according the attack frequency , scd40l , hscrp and prolactin levels were indifferent among the frequent ( 4 or more attacks / month ) and seldom ( less than 4  attacks / month ) attack groups ( table  3 ) . family history of migraine and cardiovascular disease were not associated with these parameters ( p  >  0.05 , for all).table  2soluble cd40l , hscrp and prolactin levels in migraineurs with aura and without aura subgroupsmigraineurs with aura ( n  =  23)migraineurs without aura ( n  =  27)pscd40l ( ng / ml)11.73    4.5212.08    5.9nshscrp ( ng / l)4.06    3.984.46    4.1nsprolactin ( ng / ml)9.45    4.7712.95    10.74nsns non - significant , hscrp high - sensitivity c - reactive protein , scd40l soluble cd40 ligandtable  3soluble cd40l , hscrp and prolactin levels in migraineurs with frequent ( 4 or more attacks / month ) and seldom ( less than 4 attacks / month ) headache attacksfrequent migraine attacks ( n  =  33)seldom migraine attacks ( n  =  17)pscd40l ( ng / ml)11.87    4.5514.09    6.8nshscrp ( ng / l)4.40    3.724.76    5.04nsprolactin ( ng / ml)9.70    5.7510.60    3.74nsns non - significant , hscrp high - sensitivity c - reactive protein , scd40l soluble cd40 ligand soluble cd40l , hscrp and prolactin levels in migraineurs with aura and without aura subgroups ns non - significant , hscrp high - sensitivity c - reactive protein , scd40l soluble cd40 ligand soluble cd40l , hscrp and prolactin levels in migraineurs with frequent ( 4 or more attacks / month ) and seldom ( less than 4 attacks / month ) headache attacks ns non - significant , hscrp high - sensitivity c - reactive protein , scd40l soluble cd40 ligand we consider that this is a new data related to the association of migraine and vascular diseases . soluble cd40l was suggested to be a predictor for myocardial infarction and stroke [ 2123 ] . in the studies , where the acute coronary patients were enrolled , scd40l was found as a marker of inflammatory thrombotic activity and found related with further increased cardiovascular events [ 21 , 22 ] . recently , cd40/cd40l pathway activation and a subsequent proinflamatory milieu were reported in diseases such as obesity [ 24 , 25 ] , diabetes mellitus   and hypertension . whether migraine patients constitute a low- or high - risk group for cardiovascular disease is obscure , but high - scd40l levels in migraine patients in our study support the presence of a vascular damage in migraine . cd40l belongs to the tumor necrosis family and is a transmembrane protein expressed by heamatopoetic cell types such as t lymphocytes , monocytes and platelets as well as by nonheamatopoetic cells like endothelial and smooth muscle cells . soluble form is particularly produced by platelet activation , is associated with plaque instability and is a predictor of the plaque complications [ 29 , 30 ] . moreover , cd40l is able to promote overexpression of tissue factor , a glycoprotein that has a crucial role in the activation of coagulation cascade . in order to clarify if the increase of scd40l in migraine patients is concordant with platelet activation , we compared between the mean platelet volume of two groups . it is a reliable marker of platelet activation such as platelet aggregation , secretion of thromboxane a2 , platelet factor 4 and thromboglobulin [ 32 , 33 ] . we found that the mean platelet volume of migraine patients was significantly higher than that in the controls , and it was correlated with cd40l levels in migraine . this impresses that the high scd40l levels in our study were mainly dependent on platelet activation . soluble cd40l additionally has inflammatory property including expression of adhesive molecule , chemokines and metalloproteinases , which is different from the inflammatory pathway of crp [ 21 , 27 ] . matrixmetalloproteinase 9 , whose levels are found high during migraine attacks , degrades laminin , collagen type iv , a critical component of brain blood levels . soluble cd40l also induces the secretion of other proinflammatory cytokines such as interleukin 1 ( il-1 ) , il-6 , il-8 , il-10 and tumor necrosis factor ( tnf ) from monocytes , dentritic cells , fibroblasts   and epithelial cells . tnf alpha , il-6 , il1 beta and il10 were found to be increased during migraine attacks . in the present study , since we did not measure the levels of these proinflammatory cytokines , it is not possible to conclude any association of the proinflammatory property of scd40l with the inflammation in migraine . another finding of our study is that the hscrp levels of the migraineurs and the control cases were not significantly different . there are several studies reporting modest hscrp increase in migraine patients , but this elevation was only noted in the migraine without aura group which was actually not associated with cardiovascular diseases [ 79 ] . a recent study carried on large number of case groups demonstrated no difference in hscrp levels in migraine patients and non - migraineurs . the elevation of hscrp levels is a marker of inflammatory process , especially in the cardiovascular diseases , infection and malignacies . however , as known , low crp levels can also be seen in diseases with marked tissue inflammation such as systemic lupus erythematosus . normal hscrp value in migraine should not mean that there is no inflammation or no risk of cardiovascular disease in migraine . other pathways , such as the inflammatory cd40 property , may be involved in the inflammatory process of migraine . in our study , we found similar prolactin levels between the migraine and control groups during interictal period . our results are concordant with two other studies reporting normal prolactin levels in migraine [ 41 , 42 ] . it was hypothesized that the increased dopaminergic activity is responsible from prodromal , clinical and postdromal symptoms [ 19 , 43 ] and , therefore , a decrease in prolactin levels should be expected during migraine attacks . conveniently , masoud and fakharian   found a significant decrease in prolactin levels during the headache attack in migraineurs . another study reported high prolactin levels during migraine attack , but the study was carried on subjects who had microprolactinomas . since we measured the prolactin levels only during the interictal period , we could not compare our results with these two studies . although prolactin has been reported to create a tendency to the cardiovascular diseases [ 4548 ] , our study demonstrated no correlation of prolactin with scd40l and hs - crp . it is known that increased prolactin levels in cases with prolactinoma cause obesity , insulin resistance , an increase in homocysteine levels and low - grade inflammation and subsequently a tendency to cardiovascular diseases [ 46 , 47 ] . recently , a relationship was found between prolactin levels , blood pressure and arterial stiffness , and prolactin was accused of accelerated atherosclerosis in women with early menopause . the demonstration of the intense prolactin receptor expression on advanced human coronary atherosclerotic plaques supports the role of prolactin on the development of atherosclerosis . the present study demonstrated that the scd40l levels are elevated in female migraine patients during interictal period . the small number of the groups and the omission of other hormones , such as estrogens and progesterone , which influence the biologic action of prolactin were the limitations of the study . we consider that our findings should be supported by investigations during the attack period and also in male migraineurs . further prospective studies are needed to clarify the mechanisms underlying the association between migraine and cardiovascular diseases .
the relationship of migraine with cardiovascular diseases has been clarified by many studies , and currently , migraine is suggested to be a systematic vasculopathy . 
 inflammation , thrombosis and impaired vascular reactivity are the underlying pathophysiological mechanisms of the vasculopathy . 
 in the present study , we aimed to investigate the relationship between prolactin levels and subclinical atherosclerosis risk factors such as soluble cd40 ligand ( scd40l ) and high - sensitivity crp ( hscrp ) in migraine patients during interictal period . 
 fifty female migraine patients and age - matched 25 female control cases were enrolled in the study . 
 migraine diagnosis was settled according to the ichd - ii diagnostic criteria . 
 a questionnaire was completed about the existence of vascular risk factors . 
 serum samples were used to measure scd40l , hscrp and prolactin levels . 
 no difference was found between the prolactin levels of the migraine patients and the controls . 
 the scd40l levels were significantly higher in migraine patients ( p  <  0.001 ) . 
 high - sensitivity crp levels showed no difference between the groups . 
 there was no correlation between prolactin , scd40l , and hs - crp levels in migraine patients . 
 we consider that the migraine patients are prone to subclinical atherosclerosis , but this tendency is independent of prolactin levels .