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July2007 Vol.44 Issue:      2 Table of Contents
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The Possible Role of Serum Prolactin Analysis in Diagnosis of Multiple Sclerosis

Ahmed Abou Hagar1, Yahia Zakaria2, Ahmed Osama1

Department of Neurology, Suez Canal1, Cairo2 Universities



ABSTRACT

Prolactin (PRL) belongs to the growth and lactogenic hormone family and has potent immunomodulating properties. Mild hyperprolactinemia has been found to enhance several autoimmune diseases and increased PRL plasma levels have been described in multiple sclerosis (MS). Objective As studies of PRL serum levels in MS patients have led to conflicting results we tried in this study to clarify the question of prolactin alterations in MS. Subject and Methods: We correlated serum PRL baseline value in 15 MS patients with disease course, activity and clinical severity compared with 20 sex and age- matched healthy controls. We excluded conditions leading to rise in PRL; such as pregnancy and lactation. Serum PRL levels were measured in fasting blood samples. We recorded the duration, subtypes, clinical manifestation and the expanded disability status score (EDSS) for each case of the MS patients. Results There was a statistically significant difference between patients and control groups. There was a high percentage of subjects with elevated PRL levels among the patient group(20%) (p=0.036*). There was no statistical significant relationship between the patients with elevated serum PRL levels and the duration, activity and EDSS of the disease. Conclusion The results were discussed from the fact that PRL does not seem to be relevant as an activity marker in whole MS patients. It is not clear whether PRL is primarily involved in the pathogenesis of MS or just exists as a secondary phenomenon depending on the localization of MS plaques. (Egypt J. Neurol. Psychiat. Neurosurg., 2007, 44(2): 529-534)




INTRODUCTION

 

Multiple sclerosis (MS) is a chronic demyelinating disease characterized pathologically by scattered areas of central nervous system (CNS) white matter inflammation, demyelination and gliosis. It is defined clinically by involvement of different parts of the CNS at different times. The highest incidence is between 20 and 30 years of age, and females are affected twice as often as males1.

The etiology of MS is not known, but it probably involves multiple factors, including autoimmunity as a central pathogenic mechanism.

Multiple lines of evidence support the concept that the endocrine system influences the immune system and vice versa2. In fact prolactin (PRL) has potent immunoregulatory effect3. This PRL hormone is a pituitary hormone which is also produced by certain activated lymphocytes4.

The aim of this study was designed to determine whether our diagnosed patients with MS are in a hyperprolactinemic state and whether there is any correlation between PRL level and certain clinical features of the disease.

 

SUBJECTS AND METHODS

 

15 patients with MS and 20 healthy controls were included in this study. The diagnosis of the disease was based upon clinical11 neuro-imaging and laboratory studies. The clinical evaluation of the examined cases was stressed on the following criteria; Age at onset, Duration of the disease, Course of the disease and Severity of the disease according to Expanded Disability Status Scale (EDSS).

The selected diagnosed patients with MS had to be free from conditions leading to elevated PRL level  including: Pregnancy, lactation, recent delivery or abortion, pituitary adenoma, hypothalamic disease, primary hypothyroidism, renal failure, seizures and liver cirrhosis. An extensive list of drugs including: phenothiazines, butyrophenones, benzamides, reserpine, methyldopa, opiates, estrogens, cimetidine, ranitidine, amitriptyline, nortriptyline, amoxapine and fluoxetine were considered exclusive as well.

The control group consisted of healthy individuals selected to match the patients with respect to age and gender. Control females were not pregnant or lactating and were not on  any regular medication.

 

Hormonal Analysis

Venous blood samples for hormonal analysis were collected from patient and control groups in the morning before taking their breakfast. PRL level was determined in special laboratory using the Kavoshyar  immuno-radiometeric assay test. Intra and inter-series check-up analysis were performed using the control sera.

 

Statistical Analysis

To compare the mean PRL levels in the MS and control groups, two independent sample t-tests were used. The numerical data were presented as mean and standard deviation values. Categorical data were presented as frequencies and percentages. Student's t-test was used to compare between means of the two groups. Chi-square test was used for comparisons between categorical data. Pearson's correlation coefficient was used to study significant correlations between the different variables. The significance level was set at P < 0.05.

 

RESULTS

 

Patients group

Clinical features of the examined 15 patients with MS in our study were summarized as follows:

·                     Male/female ratio was 13.3% to 86.7%.

·           The mean of age was 28.7+8.9 years (ranging from 17 to 45 years).

·           The mean duration since the onset of the disease was 5.4+3 years.

·           80% of the patients had normal serum PRL values while 20%had high prolactin levels (taking into consideration the difference between male and female normal values ♀; 6-29.9 & ♂; 4.6-21.4 ng/ml)

·           Course of the disease was secondary progressive in 26.7%, and relapsing remittent in73.3% .

·           Patients were classified according to disease activity which revealed that 26.7% were afflicted with active disease i.e.; recent relapse (<1 month), and 73.3% were afflicted with inactive disease.

·           The results of the Expanded Disability Status Scores (EDSS)7 among our patients revealed the following; mild EDSS (<3.5) in 58%, moderate (3.5-5.5) in 42% and severe (>5.5) in 6.5% of the patients.

 

Control Group

·           This group included 17 females (85%) and 3 males (15%).

·           The mean of age was 26.7+7.5 years (their age varies between 17 and 39 gears)

·                     The prolactin level was within normal.

 

Comparison between the Obtained results among MS patients and the controls

The following table (1) and figure (1) demonstrate the standard deviation values of Student's t-test concerning the mean age of the two groups.

There was no statistically significant difference between the mean ages of the two groups.

The following table (2) demonstrates the frequencies, percentages and results of chi-square test concerning the gender among the patients gender distribution among the patients and the control groups.

There was a statistically significant difference between the two groups. Patients showed a higher percentage of subjects with high prolactin level.

Table (4) Demonstrates the frequencies, percentages and the results of application of Chi-square test on disease activity among patients.

These statistical studies demonstrate that there was no statistical significant between the percentage of patients with active disease (last relapse < one month) and those with inactive disease (last relapse > one month).

The following table (5) demonstrates the mean standard deviation values and the results of student's t-test among patients concerning  their age the expanded disability stats scores (EDSS).

There was no statistically significant difference between the means age, duration and EDSS of patients with normal and high prolactin levels. Patients with high prolactin level showed a statistically significantly higher mean prolactin level measurement than those with normal level.

The following table (6) demonstrates the correlation coefficient of prolactin level and EDSS among patients.

There was no statistically significant correlation between prolactin level and EDSS.

Table 1.  

 

Patients

age

Control

age

t-value

P-Value

Mean

SD

Mean

SD

28.7

8.9

26.7

7.5

0.729

0.471

 

 

 

Fig. (1)

Table 2.

 

 

Patients

 (n=150)

Control

(n=20)

X2-

value

P-

Value

 

Frequency

%

Frequency

%

Male

2

13.3

3

15

0.019

0.471

Female

13

86.7

17

85

Table 3.

 

 

Patients

 (n=15)

Control

(n=20)

X2-

value

P-

Value

 

Frequency

%

Frequency

%

Normal

12

80

20

100

4.375

0.036*

High

3

20

0

0

* : Significant at P < 0.05

 

Table 4.

 

Last relapse

Less than a month

More than a month

x2-value

P-value

4 patients(26.7%)

11patients(73.3%)

3.267

0.071

 

Table 5.

 

Variable

Normal

(n =12)

High

(n =3)

t-value

P-value

Mean

SD

Mean

SD

Age

29.3

9.6

26.3

5.8

0.495

0.629

Duration

5.1

2.9

6.3

4

-0.607

0.554

Prolactin level

15.2

5.7

37.1

7.3

-5.699

<0.001*

EDSS

3.3

2.3

5

4

-0.999

0.336

* : Significant at P < 0.05

 

Table 6.

 

 

Correlation coefficient (r)

P-value

EDSS

0.340

0.215

*: Significant at P ≤ 0.05

 

 


DISCUSSION

 

Prolactin (PRL) belongs to the growth and lactogenic hormone family and has potent immunomodulating properties. Mild hyperprolactinemia has been found to enhance several autoimmune diseases. An increase in prolactin plasma levels have been described in the experimental multiple sclerosis, while the PRL antagonist bromocriptine was able to suppress the disease of MS5.

In a trial to determine whether patients with MS show evidence of hyperprolactinemia it was found that patients with MS had slightly but significantly higher prolactin levels at baseline than controls, however, the values were within the normal range. These findings suggested that prolactin may play a role in the immunology of MS6.

The objective of this study was to clarify the clinical features of MS patients in relation to the PRL levels in their serum. Prolactin plasma levels were determined in 15 patients with MS and in 20 healthy subjects. Serum prolactin levels were found to be significantly higher in MS patients. One fifth of the MS patients had mild to moderate hyperprolactinemia compared to healthy subjects. These findings are compatible with data from other studies7, which suggested that prolactin may play a role in the immunology of MS while Kera et al.10 showed a PRL rise during relapse which was associated with hypothalamic lesions in only 50% of those patients. In another study demyelinating lesions of fiber bundles in and adjacent to the hypothalamus were found which may be the basis for autonomic and endocrine alterations in MS patients9. It has been suggested that disruption of inhibitory fibers might cause hyperprolactinemia in MS12. However, Heesen et al.5 found no correlation of baseline PRL values with disease course or activity.

        Van de Kar13 mentioned that PRL has potent immunomodulatory properties, it is considered as an acute phase reactant as well. Circulatory levels of this hormone increase in a nonspecific manner in many inflammatory conditions as well as the primary physiological context for PRL during pregnancy and lactation. These states can be considered as states of chronic stress, and during these times, PRL increases, leading to an adaptive stress response14.

We may say that the serum levels of PRL hormone increase in MS  in a nonspecific manner like many inflammatory and physiological conditions. Mild hyperprolactinemia has been found to enhance several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythromatosis and autoimmune thyroiditis8.

We may conclude that  serum PRL determination does not seem to be relevant as an activity marker in the whole MS patients but it could be related to  the localization of the demyelinating lesions in some patients taking into consideration the immunomodulatory properties of this hormone.

REEFRENCES

 

1.      Miller JR: Multiple sclerosis. In : Rowland LP ed. Merrits' neurology. 3rd ed Philadelphia: Lippincott. Williams and Wikns, 2000; pp 773-791

2.      Besedovsky HO, Del Rey A (1996): Immune-neuro endocrine interaction: facts and hypotheses. Endo Rev 1996 :17: 64-102.

3.      Mellai M Giordano M; D'Alfonso S (2003); Prolactin and prolactin receptor gene polymorphism in multiple sclerosis and systemic lupus erythematos is. Hum Immunol. 2003 64 (2): 274-284.

4.      McMurray (2001): Bromocriptine in rheumatic and autoimmune disease. Semin Arthritis Rheum. 2001, 31 (1) 21-32.

5.      Hessen C, Gold SM, Bruhn A, Schulz KH (2002): Prolactin stimulation in multiple sclerosis an indicator of disease subtypes and activity: Endocr. Res: 2002 (28) (1-2): 9-18,

6.      Azar ST, Yamout B (1999): Prolactin secretion is increased in patients with multiple sclerosis. Endocr. Res 1999  25 (2) 207-214

7.      Mohammad H. Harirchlan, Mohammad A. Sahralan and Afsoneh Shiranl 2006: Serum prolatin level in patients with multiple sclerosis. A case control study : Med Sci Monit, 2006 : 12 (4); 177-180

8.      Chikanza IC (1999): Prolactin and neuroimmunomodulation in vitro and in vivo observations. Ann NY Acad Sci 1999; 87 (6) 119-130.

9.      Yamasaki K; Horiuchi I; Minohara M; Osoegawa M; Kawano Y; Ohyagi Y; Yamada T; Kira J; (2000)  Hyperprolactinemia in optico-spinal multiple sclerosis. Intern Med. 2000 Apr;39(4):296-9.

10.    Kira J, Harada M, Yamaguchi Y, Shida N, Goto I; (1991) Hyperprolactinemia in multiple sclerosis. J Neurol Sci. 1991 Mar;102(1): 61-6.

11.    Poser CM, Paty DW, Scheinberg L et al.(1983)New diagnostic criteria for multiple sclerosis: guideline for research protocols. Ann Neurol, 1983; 13: 227–31

12.    Draca S, Levic Z (1996): The possible role of prolactin in the immunopathogenesis of multiple sclerosis. Med Hypotheses, 1996; 47(2): 89–92

13.    Van de Kar LD, Blair ML(1991): Forebrain pathways mediating stress-induced hormones secretion. Neuroendocrinol, 1991; 20(1): 1–48

14.    Duquette P (2002): Hormonal factors in multiple sclerosis. Int MS J, 2002; 9(1):16–25


الملخـص العربى

 

دراسة عن نسبة تواجد هرمون البرولاكتين فى الدم كمحاولة لتأكيد أو نفي تشخيص

مرض التصلب المتناثر فى الجهاز العصبي

 

كان الغرض من هذا البحث هو معرفة الدور الذي يلعبه زيادة هرمون البرولاكتين في مرضي التصلب المتناثر في الجهاز العصبي وإمكانية الاعتماد على هذه الدراسة في تشخيص هذا المرض.

تناول البحث فحس 15 مريضاً تم تشخيصهم بواسطة الرنين المغناطيس بأنهم مصابون بمرض التصلب المتناثر في الجهاز العصبي . كما تم فحص 20 شخصاً من الأصحاء بعد استبعاد السيدات الحوامل والمرضعات والأشخاص المصابون بأمراض الغدة النخامية والسريرية والدرقية أو تليف بالكبد واعتبرت هذه المجموعة كمجموعة ضابطة للبحث. أجريت الفحوص الإكلينيكية على المرضي وتم تسجيل بيان عن كل حالة متضمناً: مدة المرض من بدء ظهوره وأعمار المرضي عند ظهور أول أعراض المرض، كيفية تسلسل ظهور الأعراض المرضية، مدي تطور مضاعفات هذا المرض وحدته عند كل مريض على حده.

أخذت عينات من دم مجموعتين المرضي والأصحاء وتم تحليلها في معامل متخصصة لمعرفة نسبة هرمون ثم البرولاكتين. بعد تدوين النتائج التي تم الحصول عليها ثم أجريت دراسة إحصائية على هذه النتائج أخذين في الاعتبار مقارنة نتائج الأفراد المرضي بقرنائهم من الأصحاء من حيث العمر والجنس.

أظهرت نتائج الدراسة الإحصائية وجود زيادة نسبة هرمون البرولاكتين عند المرضى لكن لا توجد علاقة مباشرة بين هذه ألزيادة ومدي حدة هذا المرض ومدته ومضاعفاته.

نوقشت نتائج هذا البحث من حيث أنه لا يمكن الاعتماد الفردي على زيادة نسبة هذا الهرمون لتشخيص هذا المرض. كما أنه لا يمكن القول بأن هذه الزيادة هي المسببة لحدوث هذا المرض ولكن من الممكن القول بأن زيادة نسبة هذا الهرمون في هؤلاء المرضي قد تعتمد على مدي تواجد التغيرات الباثولوجية لهذا المرض في الأجزاء المختلفة للجهاز العصبي.



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