THE EFFECT OF BROMOCRIPTINE ON C-REACTIVE PROTEIN IN WOMEN WITH HYPERPROLACTINEMIC AMENORRHEA

C-reactive protein has become the subject of avid interest in recent years. Increased concentrations of C-reactive protein (CRP) became widely accepted as a risk factor of many inflammatory diseases including atherosclerosis, ischemic vascular diseases, type 2 diabetes mellitus, hypertension and colon cancer. Data evaluating the concentration of CRP in hyperprolactinemic condition and the effect of bromocriptine on CRP concentration are not available. Thus the present study was designed to measure the concentration of CRP in a number of women with hyperprolactinemic amenorrhea and to evaluate the effect of bromocriptine on CRP concentration. The study tackled sixty women, who had amenorrhea for at least three months and serum prolactin concentration at least twice the upper limit of normal values. Bromocriptine is administered in a daily dose of 2 (2.5 mg) tablets. Serum prolactin and serum CRP were assessed before and after bromocriptine administration, using commercial kits. Mean CRP concentration of the control group was 1.38±1.85 mg/L which is statistically lower than value of 6.35±4.62 mg/L of the patients before bromocripine therapy (P<0.001). A significant drop of CRP (from a mean of 6.35±4.62 mg/L to a mean of 2.73±3.14 mg/L) was obtained after treatment with bromocriptine (P<0.001). The correlation between serum prolactin level and serum CRP level before and after bromocriptine administration was not statistically significant: r= 0.24, P>0.05 and r = 0.12, P>0.2, respectively. The present study showed that women with hyperprolactinemic amenorrhea is associated with increased level of CRP and therapy with bromocriptine significantly reduced CRP, suggesting a possible anti-inflammatory action of bromocriptine in addition to prolactin


INTRODUCTION
yperprolactinemia is the most common endocrine disorder of the hypothalamic-pituitary axis, with a prevalence of 0.4% in an unselected adult population to 9-17% in women with reproductive disorders. [1]It is characterized by elevated serum levels of the hormone prolactin.It occurs in both genders, although it is the most prevalent disorder among reproductive aged women. [2]It was demonstrated that patients with hyperprolactinemia have low-grade inflammation. [3]The interrelationship between prolactin and the immune system have been elucidated in the last decade, opening new important horizons in the field of the immunoendocrinology. [4]Prolactin is secreted not only by anterior pituitary gland but also by many extrapituitary sites including the immune cells, whether endocrine or autocrine.Prolactin exerts profound effects on a wide range of tissues, with over 300 effects described in vertebrates. [5]Multiple lines of evidence support the concept that the high levels of prolactin has a pathogenic role in rheumatic and autoimmune diseases including, rheumatoid arthritis, [6] systemic lupus erythematosus, [7] Reiters syndrome, [8] psoriatic arthritis, [9] celiac disease, type 1 diabetes mellitus, experimental allergic encephalomyelitis, uveitis, and thyroid disease. [10,11]In vitro [12] and in vivo [13] studies demonstrated that prolactin exhibits immunostimulatory properties and can modulate inflammatory responses.Based on these data patients with hyperprolactinemia might present increased markers of systemic inflammation such as C-reactive protein.C-reactive protein (CRP) is a plasma protein; an acute phase protein produced by the liver.It is a member of the pentraxin family of proteins.It should not be confused with C-peptides or protein C. [14] It is present in the sera of acutely ill patients and that is able to bind the C-polysaccharide on the cell wall of streptococcus pneumonia was first described in 1930. [15]CRP rapidly increases within hours after tissue injury, and it is suggested that it is part of the innate immune system and contributes to host defense. [16]CRP has become the subject of avid interest in recent years.Increased concentrations of C-reactive protein (CRP) became widely accepted as a risk H factor of many inflammatory diseases including atherosclerosis, [17,18] myocardial infarction, ischemic stroke, peripheral vascular disease and sudden cardiac death [19][20][21] and metabolic syndrome. [22,23]Several studies demonstrate that CRP can be used to predict the development of type 2 diabetes mellitus. [24,25]C-reactive protein levels are associated with future development of hypertension, which suggests that hypertension is in part an inflammatory disorder. [26]CRP is elevated in patients with colon cancer indicating that anti-inflammatory drugs could lower colon cancer risk. [27,28]Bromocriptine, introduced in 1971, is a dopamine agonist, [29] the original preparation against which newer dopamine agonists are compared.It is effective in suppressing prolactin hypersecretion, reducing prolactinoma size, and restoring gonadal function. [30]Because of its short half life (3.3hours), bromocriptine may require multiple dosing throughout the day. [31]Several trials demonstrated that the dopaminergic agonist bromocriptine appears to have therapeutic effects in rheumatic and autoimmune diseases which are associated with hyperprolactinemia including, rheumatoid arthritis, [32] systemic lupus erythematosus, [33] Reiter´s syndrome, psoriatic arthritis and uveitis. [6]Trial data evaluating the concentration of CRP in hyperprolactinemic conditions and the effect of bromocriptine on CRP concentration are not available.Thus the present study was designed to measure the concentration of CRP in a number of women with hyperprolactinemic amenorrhea and to evaluate the effect of bromocriptine on CRP concentration.

PATIENTS AND METHODS
The study was an open, 8-week period trial conducted to measure the concentration of Creactive protein and to evaluate the effect of bromocriptine (Parlodel, 2.5 mg tablets, manufactured by NOVARTIS PHARMA S.A.E., Cairo, under licence from Novartis pharma AG., Basle, Switzerland) on the concentration of CRP in women with hyperprolactinema, who were collected from Al-Batool Teaching Hospital for Gynaecology and Obstetrics in Mosul city.The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation of Nineveh Health Administration and with the Helsinki Declaration.The study tackled sixty women, 21 to 39 years of age who had amenorrhea for at least three months and serum prolactin concentration at least twice the upper limit of normal values, at least four weeks after the discontinuation of any previous therapy.Women were excluded from the study that shows the presence of a pituitary macroadenoma, any disorder that could prevent normal menstruation, hyperprolactinemia related to polycystic ovary disease, thyroid or adrenal disorders, renal or hepatic disease and a history of allergy to ergot derivatives.Women were also excluded who had used any drugs that affect secretion of prolactin from the pituitary such as neuroleptics.Bromocriptine is administered in a daily dose of 2 (2.5 mg) tablets.Another forty apparently healthy women whose age ranged from 21 to 38 years were included in the study as a control group.Serum prolactin was measured at baseline and at the end of 8-week of bromocriptine administration (at the end of the trial) with commercially available Kit (immunoradiometric assay) (IRMA), Kit, Beckman Coulter Company-Czech Republic.The upper range of normal serum prolactin level was considered 16 µg/L.Serum CRP was assessed by using Chemelex, S.A. kit (Pol.Ind.Can Castells.C / industria 113.Nau J) before and after bromocriptine administration.The upper range of normal serum CRP level was considered up to 6 mg/L.Serum Prolactin and CRP were also measured in the control subjects.All values were quoted as the mean±SD.Paired t-test was used to compare serum prolactin and CRP level at baseline and after treatment.Unpaired t-test was used to compare between serum CRP concentration and serum prolactin concentration of the patient group before treatment and those of the control group.Pearson correlation coefficient was performed to find the relationship between prolactin levels and CRP before and after treatment with bromocriptine.

RESULTS
A significant reduction of serum prolactin level was demonstrated after treatment with bromocriptine (P<0.001)(Table-1).Mean CRP concentration of the control group was 1.38±1.85mg/L which is statistically significantly lower than value of 6.35±4.62/L of the patients before bromocripine therapy (P<0.001) and mean serum prolactin levels of the control group was 6.46±4.12µg/L which is statistically significantly lower than value of 48.04±24.12µg/L of the patients before bromocriptine therapy (P<0.001).
The correlation between serum prolactin level and serum CRP level before and after bromocriptine administration were: r= 0.24, P > 0.05 and r = 0.12, P>0.2, respectively (Table -3).

DISCUSSION
[36] The present study demonstrated that hyperprolactinemic amenorrhea condition is associated with an inflammatory state, as represented by elevated serum CRP level, an important marker of inflammation.Treatment with bromocriptine reduced significantly the level of CRP.40] Thus, the findings in the present study may be an of clinical importance as CRP is thought to be independent risk factor for cardiovascular disease. [41]The mean CRP reported in the present study is 6.35 mg/L is in the range of increased risk for cardiovascular disease whereas the mean value of CRP of 1.38 mg/L in the control group is in the range of low cardiovascular risk.The risk of serum CRP levels for cardiovascular disease is as follows: low risk <1mg/L, average risk 1-3 mg/L and high risk > 3mg/L. [42]Bromocriptine in the present study significantly reduced the level of CRP after 8 week interval.Bromocriptine is dopamine agonists that suppress pituitary secretion of prolactin.The mechanism by which bromcriptine reduce CRP concentration is not clear, it may be due to suppressing circulatory prolactin, and through this mechanism, has the potential to suppress inflammatory reaction caused by prolactin, and through this mechanism, the stimulating effect of prolactin on the hepatocytes to synthesized CRP is suppressed resulting in the reduction of CRP level.But the present study demonstrated a very weak, non significant relation between serum prolactin and serum CRP level before and after bromocriptine administration.This may indicate that another mechanism may be involved in the reduction of CRP by bromocriptine other than its effect on prolactin secretion, suggesting an anti-inflammatory effect for bromocriptine in addition to prolactin lowering effect.The anterior pituitary hormone prolactin has a pathogenic role in rheumatic and autoimmune diseases including rheumatoid arthritis, systemic lupus erythematusus, Reiters syndrome, psoriatic arthritis and uveitis.Conversely, the dopaminergic agonist bromocriptine appears to have therapeutic effects through suppression of pituitary prolactin secretion and perhaps through actions on peripheral dopamine receptors. [6]The reduction of the elevated CRP in the present study may explain the beneficial therapeutic effect of bromocriptine reported in the above diseases in part by its effect on CRP a marker of inflammation.In addition to bromocriptine which is reported in the present study to reduce the concentration of CRP in women with hyperprolactinemic amenorrhea.A number of other agents have been reported by other studies to reduce the concentration of CRP in other diseases.Reduction in CRP levels has been seen following treatment with statins; a group of hypolipidemic agents including pravastatin, simvastatin, and atorvastatin. [43]In addition many other drugs have been found to affect the concentration of CRP including azetimibe, [44] aspirin and clopidogrel, [45] and the antihypertensive drug valsartan. [46]n conclusion: The present study showed that women with hyperprolactinemic amenorrhea are associated with increased level of CRP and therapy with bromocriptine significantly reduced CRP, suggesting a possible antiinflammatory action of bromocriptine in addition to prolactin lowering effects.