INTRODUCTION

 

Multiple sclerosis (MS) is a multifactorial demyelinating and immune-mediated neurological disease.¹ Pituitary secretion of prolactin was found to be not only a hormone but also an immunomodulating molecule with an array of effects. Prolactin regulates the maturation of CD4-CD8- thymocytes into CD4+ and CD8+ T cell and has anti-apoptotic effects on transitional B cells, it helps in antigens and mitogens, enhancement of antigen-presenting cell development expressing major histocompatibility complex class II and costimulatory molecules CD40, CD80, CD86.²

Moreover, Prolactin increases immunoglobulin production, up-regulation of Th-l cytokines, and enhancement of interleukin 2 effects on lymphocytes.³ PRL receptors (PRL-Rs) are distributed throughout the immune system and are included as members of the cytokine receptor superfamily.⁴ Mild hyperprolactinemia has been found to be associated with autoimmune diseases in human as well as in animal models.⁵

Previous studies that evaluated the serum levels of prolactin in MS patients yielded conflicting results. Kira and colleagues⁶ reported a mild to moderate increase in prolactin levels in 30% of MS patients also, Azar and

 

Yamout⁷ described high activity of the hypothalamic-pituitary axis by demonstrating a higher prolactin-stimulatory capacity after thyrotropin-releasing hormone test in MS patients. In 1997 Wei and Lightman⁸ reported normal prolactin levels and hypothalamo-pituitary-adrenal function in MS patients, and Heesen and colleagues⁹ showed no correlation between baseline prolactin values and MS activity or course.

Thus, it is currently not clear if altered levels of prolactin documented in MS patients are a primary phenomenon in the pathogenesis of the disease, as in experimental model of the disease⁹, or if hyperprolactinemia occurs as a result of a specific endocrine axis involvement depends on localization of MS plaques. We sought to evaluate the possible correlation of prolactin level in a group of Egyptians with different MS clinical presentations.  

 

Aim of Work:

To evaluate possible correlations of Prolactin level with different clinical presentations of the disease.

 

SUBJECTS AND METHODS

 

Thirty-four patients with MS who presented to Mansoura Neurology outpatient clinic for follow up or who were admitted to our department in relapse besides an age and sex matched healthy 30 subjects as control group were included in our study.

The diagnosis of MS was based on the recommended diagnostic criteria for multiple sclerosis; guidelines from the International Panel on the diagnosis of multiple sclerosis.¹⁰ The Expanded Disability Status Scores (EDDS) was used to evaluate the clinical status.

Exclusion criteria (for both patients and controls) included (a) subjects with another condition that may affect PRL level as pregnancy, recent delivery or abortion, lactation, pituitary disorders, endocrinal disturbance, chronic renal disease, liver cirrhosis, epilepsy, and (b) patients currently on medications that may affect PRL level like cimetidine, phenothiazine, contraceptive pills, reserpine, fluoxetine and tricyclic antidepressant, and antipsychotics.

Fasting early morning venous blood samples were collected using standard sampling tubes and stored at 2-8°c. Serum prolactin concentration was measured using the Elecsy prolactin II assay (Roche diagnostics, USA).¹¹ It is an electrochemiluminescence immunoassay (ECLIA) for quantitative determination of prolactin in human serum and is intended for use on Elecsy 2010 analyzers.

 

Statistical Analysis

Data were collected and calculated using the SPSS v.16 for windows. Two independent sample t-tests were used to compare prolactin level between patients and controls. Pearson’s correlation coefficient was used to study correlation between different variables. The numerical data were presented as mean and standard deviation; other data were evaluated as frequencies and percentage. The significant level was set as P value ≤0.05.

 

RESULTS

 

A total of 34 MS patients and 30 age and sex matched healthy subjects as control group were included in our study. There was no statistically significant difference between patients and controls regarding age, sex and prolactin level.

Only four patients (11.8%) had a secondary progressive multiple sclerosis (SPMS) while the remaining 30 patients (88.2%) had a relapsing remitting multiple sclerosis (RRMS). Considering disease activity, out of the patients with RRMS, sixteen patients (53.33%) were in active relapse (less than one month) and the remaining fourteen patients (46.67%) were in remission. The median duration of the disease was 5 years; ranging from 1-14 years. Nineteen patients (55.9%) including the two who having the high prolactin level had disease duration less than 5 years, while 15 patients (44.1%) suffered for more than 5 years. Regarding the Expanded Disability Status Scores (EDDS), 19 patients had EDDS less than 4 and the remaining above four (Tables 1 and 2).

There were no statistically significant differences between patients with high and those with normal prolactin levels regarding the age, gender, type of the disease, EDDS and the duration of disease. Correlation analysis confirmed significant dual influence between disease duration and EDDS and age versus disease duration (Table 3).

 

Table 1. Clinical characteristics of the multiple sclerosis patients.

 

EDDS  scale	Cases (n=34) n (%)
1.5	1(2.90%)
2	2 (5.90%)
2.5	3(8.80%)
3	3 (8.80%)
3.5	7(20.60%)
4	3(8.80%)
4.5	6 (17.60%)
5	4(11.80%)
5.5	1(2.90%)
6	3(8.80%)
6.5	1(2.90%)
Type of MS - PRMS - RRMS	4(11.80) 30(88.20)
Duration  in years - Median - Minimum  -maximum	5 1-14

EDDS Expanded Disability Status Scores, PRMS progressive relapsing multiple sclerosis, RRMS relapsing remitting multiple sclerosis

Table 2. Demographic and clinical characteristics of MS patients in relation to Prolactin level.

 

Demographic and clinical findings	Prolactin levels		Test of significance Fisher exact test
	Normal (n=32) No (%)	Increased (n=2) No (%)
Age in years <35 >35	21(65.60%) 11(34.4%)	1(50%) 1(50%)	p= 1
Gender Male Female	18(56.20%) 14(43.80%)	1(50%) 1(50%)	p= 1
Type of MS PRMS RRMS	4(12.50%) 28(87.50%)	0(0%) 2(100%)	p= 1
EDSS Scale <4 >4	18(56.20%) 14(43.80%)	1(50%) 1(50%)	p= 1
Duration of MS <5 years >5 years	17(53.10%) 15(46.90%)	2(100%) 0(0%)	p=0.4

MS Multiple Sclerosis, RRMS Relapsing Remittent Multiple sclerosis, PRMS Progressive Relapsing Multiple Sclerosis

 

Table 3. Correlation between the duration of MS, EDDS and age of the patients.

 

		Prolactin	EDDS	Duration Years	Age
Prolactin	Correlation	1	0.198	-0.159	0.056
	Sig. (2-tailed)		0.261	0.369	0.684
	N	56	34	34	56
EDDS Scale	Correlation	0.198	1	0.505**	0.245
	Sig. (2-tailed)	0.261		0.002	0.162
	N	34	34	34	34
Duration Years	Correlation	-0.159	0.505**	1	0.601**
	Sig. (2-tailed)	0.369	0.002		0.000
	N	34	34	34	34
Age	Correlation	0.056	0.245	0.601**	1
	Sig. (2-tailed)	0.684	0.162	0.000
	N	56	34	34	56

EDDS Expanded Disability Status Scores, Sig. Significance, ** Correlation is significant at the 0.01 level (2-tailed).

 

DISCUSSION

 

Multiple sclerosis is chronic inflammatory demyelinating diseases affecting the CNS, in which the immune system attacks the white matter and eventually leads to disability and at worst, paralysis.¹² It affects females twice as often as males, mainly between 20 and 30 years of age.¹³ The ethiopathogenesis of MS is unknown, but the most accepted theory is that MS is mediated by autoreactive lymphocytes.^14,15

Prolactin exists in three isoforms, partially due to variation in post translational modification. The variants have different receptor binding and biological activity; the three main PRL isoforms are the monomeric (Free little PRL), big PRL and big (macro) PRL.¹⁶ The most biologically potent isoform is the monomeric. ¹⁷ The cytokines interleukin 1, 2 and 6 stimulate prolactin secretion, while interferon-α (INF-α) and endothelin-3 are inhibitory cytokines.¹⁸

Moshirzadeh and colleagues¹³ analyzed the sera of 58 patients for prolactin level and found an increased prevalence of hyperprolactinemia among MS patients compared with healthy sex and age matched controls, as well as the possible association between hyperprolactinemia in female patients and the secondary-progressive type of disease. In the current study, we did not find significant higher prolactin level in MS patients. Also for those whom experienced higher prolactin level, they suffered RRMS course.

Again, there were no statistically significant differences between patients with higher prolactin level and those with normal level regarding age, gender, type of disease, EDDS and duration of disease. These finding was in harmony with Hessen and colleagues⁹, who found no correlation of baseline prolactin values with disease course and activity. However, these data was in contrary to other studies^7,19,20, who declared that hyperprolactinemia might play a role in the immunology of MS.

It has been reported 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 response.²¹

Although our study has limitations as the small number of patients, it seems that hyperprolactinemia may not be involved in the pathogenesis of multiple sclerosis, yet its level may be altered as many other inflammatory markers and phase reactant.

Conclusion

Our study results suggest no association between elevated titers of prolactin and types of multiple sclerosis. Prolactin may not be involved in the pathogenesis of multiple sclerosis; it may be coexisting or may be a result of CNS demyelination as many inflammatory markers in MS. Further studies with larger subjects and combining clinical data and CNS imaging are needed to evaluate its biomarker value and its relation to the clinical features of the disease.

 

[Disclosure: Authors report no conflict of interest]

 

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