|Year : 2013 | Volume
| Issue : 1 | Page : 12-17
Role of prolactin in pemphigus vulgaris
Afaf Helmy1, Mervat Azab2, Mohamed Abd El-Kader1, Amani Nassar1, Hend Embaby1
1 Department of Dermatology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||01-Sep-2012|
|Date of Acceptance||06-May-2013|
|Date of Web Publication||23-Jun-2014|
MD, Department of Dermatology, Faculty of Medicine, Zagazig University, Zagazig
Source of Support: None, Conflict of Interest: None
Prolactin (PRL) has been shown to have immunomodulatory as well as lactogenic effects. Generally, it is known that PRL may also play a role in the activity of autoimmune diseases such as pemphigus, systemic lupus erythematosus, and rheumatoid arthritis.
The aim of this study was to estimate serum PRL levels in pemphigus vulgaris (PV) patients and determine the presence of any correlation between its levels and the extent of affected body surface area or type of involvement.
Forty serum samples from 20 PV patients and 20 healthy individuals as controls were collected. Serum PRL levels were measured using an electrochemiluminescence immunoassay.
Hyperprolactinemia was found in 15% of PV patients and was absent in controls. However, this showed no statistically significant difference between serum PRL levels in PV patients and controls (P=0.4). Serum PRL levels were highest in patients with mucocutaneous involvement, followed by in those with mucosal involvement, and were the least in those with cutaneous involvement. However, there was no statistically significant difference between the three types of involvements and PRL levels (P=0.95). A statistically highly significant correlation between serum PRL levels and the extent of body surface area involvement was found (P<0.001).
PRL may serve as a useful biological marker of PV activity. Therefore, in severe refractory cases of PV, estimation of serum PRL levels should be carried out, as PRL-lowering drugs serve as useful adjuvant therapy in PV treatment.
Keywords: hyperprolactinemia, pemphigus, prolactin
|How to cite this article:|
Helmy A, Azab M, El-Kader MA, Nassar A, Embaby H. Role of prolactin in pemphigus vulgaris. Egypt J Dermatol Venerol 2013;33:12-7
| Introduction|| |
Prolactin (PRL) is a neuropeptide that performs a double action: the first as a hormone, because of pituitary production, and the second as a cytokine, by means of an extrapituitary production 1. In human beings, the most commonly known function of PRL is the hormonal action that stimulates final mammary development and ensures galactopoiesis 2.
Most immune cells secrete PRL, which modifies T and B lymphocyte functions, inhibits lymphocyte apoptosis, and enhances autoantibody production 3. Persistent mild-to-moderate hyperprolactinemia impairs the negative selection of autoreactive B lymphocytes occurring during B-cell maturation into fully functional B cells 4.
Pemphigus vulgaris (PV) is a blistering autoimmune disease caused by IgG autoantibodies that bind mainly to Dsg-3 5.
Within its normal values, PRL acts as an immunomodulatory hormone, but its oversupply shifts the balance in the immune response toward higher activity of immune cells. Increased serum PRL levels have been described in several systemic autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, as well as in organ specific autoimmune diseases such as pemphigus, diabetes mellitus type-I, and Graves’ disease 6.
The aim of this study was to estimate serum PRL levels in PV patients and determine the presence of any correlation between its levels and the extent of affected body surface area (BSA) or type of involvement.
| Patients and methods|| |
This study was carried out on two groups: the patient group and the control group. The patient group included 20 patients of PV (14 women and six men; age 23–76 years).
PV patients were selected from the outpatient clinic of the Department of Dermatology and Venereology, Zagazig University Hospital, during October 2010 to September 2011. The diagnosis was based on both clinical and histopathological examinations. At the time of enrollment, all patients had active disease and none of them had received either a local or a systemic treatment of PV.
The control group included 20 healthy volunteers matched for age and sex with the patients (14 women and six men; age 27–71 years).
The exclusion criteria in both groups were pregnancy, breastfeeding, and evidence of renal, hepatic, endocrinopathic, or psychiatric disease. A complete blood analysis was performed for all participants to exclude these diseases. The use of any concomitant medication known to affect PRL levels (such as α-methyldopa, reserpine, digoxin, haloperidol, and phenothiazines) was not permitted during the study.
All participants gave a written informed consent before inclusion into the study. The study was approved by the hospital ethics committee.
A dermatological examination was carried out to determine the type of pemphigus and the extent of involvement (mucosal, cutaneous, or mucocutaneous). The involved BSA was then calculated using the Lund and Browder chart 7.
Venous blood samples (3 ml) from the anticubital vein were drawn from the participants between 8:00 and 10:00 a.m. All measurements for women were taken during the premenstrual phase of their menstrual cycle.
The participants had been fasting and resting for at least 30 min after which a cannula was introduced with minimal trauma into the vein. The blood samples were drawn after another 30 min. This interval of 30 min was chosen because PRL is a stress hormone that is released in repeated pulses and has a biological half-life of 20–30 min.
These samples were collected into Wasserman tubes (plain plastic sample collecting tubes) and allowed to clot for 30 min. They were then centrifuged for 15 min at 2000g at room temperature; the serum was collected and stored at −20°C until analysis.
Serum PRL levels were determined by the electrochemiluminescence immunoassay (ECLIA) using a ‘Cobas e 411’ immunoassay analyzer (USA) and Elecsys Prolactin II reagent kits (USA).
In this study, data were checked, entered, and analyzed using Statistical Package for Social Sciences (SPSS, version 17; SPSS Inc., Chicago, Illinois, USA). Data were expressed as mean±SD for quantitative variables or numbers and as percentages for categorical variables.
| Results|| |
PV patients were further subdivided according to the type of involvement into three groups: the mucocutaneous PV group, which included 12 patients (60%); the mucosal PV group, which comprised five patients (25%); and the cutaneous PV group, which included three patients (15%).
According to the Lund and Browder chart, the approximate percentage of BSA involvement ranged from 6 to 52%, with a mean±SD of 29.87±12.77. PV patients were also subdivided according to the percentage of BSA involvement as follow: patients with less than 20% BSA involvement (seven patients, 35%), those with 20–39% BSA involvement (nine patients, 45%), and those with 40% or more BSA involvement (four patients, 20%).
In the present study, serum PRL levels in PV patients ranged from 2.7 to 45.9 ng/ml, with a mean PRL level±SD of 14.5±12.5. In contrast, serum PRL levels in controls ranged from 4.7 to 12.6 ng/ml, with a mean PRL level±SD of 8.39±2.5. The normal range of serum PRL levels among men is 4.6–21.4 ng/ml and that in nonpregnant, nonlactating women is 6–29.9 ng/ml.
The parametric Mann–Whitney U-test was used to establish the difference in PRL levels between patients and controls [Table 1]. No statistical significant differences were found between the two groups as regards serum PRL levels (P>0.05).
|Table 1: Comparison between patients and controls as regards serum prolactin levels|
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A comparison was made between serum PRL levels of male patients and those of controls but the result was not statistically significant [Table 2]. The same comparison was carried out between female patients and controls but was also found to be nonsignificant [Table 3].
|Table 2: Relationship between male patients and control as regards serum prolactin levels|
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|Table 3: Relationship between female patients and controls as regards serum prolactin levels|
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As regards the relation between the type of involvement and serum PRL levels, this study showed that the mean±SD serum PRL levels were highest in patients with mucocutaneous involvement but without any statistical significant difference (P>0.05) [Table 4].
|Table 4: Relation between the type of involvement and serum prolactin levels|
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A high statistically significant difference (P<0.001) was found when serum PRL levels of each group of the patients (when divided according to BSA involvement) were compared separately with the percentage of BSA involvement. Serum PRL levels in patients with BSA involvement between 20 and 39% were higher than in those with BSA involvement less than 20%, whereas serum PRL levels in patients with BSA involvement of 40% or more were higher than those in both groups [Table 5].
|Table 5: Relation between body surface area involvement and serum prolactin levels|
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In general, a positive correlation was found between the BSA involvement and serum PRL levels and was statistically highly significant (P<0.001) [Table 6].
|Table 6: Correlation between body surface area involvement and serum prolactin levels|
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In this study, three patients (all female) were found to be hypoprolactinemics, whereas none of the controls were hypoprolactinemic [Table 7].
| Discussion|| |
PRL is a peptide hormone produced by lactotroph cells of the anterior pituitary gland and is secreted in a pulsatile manner 8. PRL is also secreted by many extrapituitary sites, including the neurons, brain, prostate, decidua, mammary gland, endothelial cells, skin, adipose tissue, and immune cells 9.
The primary function of PRL is to enhance breast development during pregnancy and induce lactation. Some studies support the idea that PRL is also an immunoregulatory hormone 10. PRL receptors have been found on human T lymphocytes and B lymphocytes, and some data support the dependency of T lymphocytes on PRL for maintenance of immunocompetence. The role of PRL in immune reactions is stimulating – its presence significantly increases the ability of immune cells to proliferate and produce cytokines 11.
Hyperprolactinemia has been observed in some autoimmune diseases such as systemic lupus erythematosus, type 1 diabetes mellitus, Graves’ disease, and multiple sclerosis. This correlation could depend on a coordinated bidirectional communication between the neuroendocrinal disorder and immune disease 6.
PV is a blistering autoimmune disorder in which the role of hyperprolactinemia is still being researched 12.
Kavala et al. 13 were the first to study the relationship between PV and serum PRL levels; they concluded that a positive correlation between serum PRL levels and disease activity exists. Later, Fallahzadeh et al. 14 conducted another study in which elevations of serum PRL levels in patients with PV were detected, especially among those with severe PV.
In the present work, 35% of PV patients showed an approximate percentage of BSA involvement of less than 20% according to the Lund and Browder chart, 45% of patients showed a BSA involvement between 20 and 39%, and only 20% of patients a showed BSA involvement of 40% or more. The approximate percentage of BSA involvement ranged from 6 to 52%, with a mean±SD of 29.87±12.77.
Fallahzadeh et al. 14 found that 45.8% of PV patients showed an approximate percentage of BSA involvement of less than 20% according to the Lund and Browder chart, 4.2% of patients showed a BSA involvement between 20 and 39%, and 50% of patients showed a BSA involvement of 40% or more.
The normal range of serum PRL levels in men is 4.6–21.4 ng/ml and that in nonpregnant, nonlactating women is 6–29.9 ng/ml. During this work, serum PRL levels in PV patients were 2.7–45.9 ng/ml, with a mean value±SD of 14.5±12.5, whereas those in the control group were 4.7–12.6 ng/ml, with a mean value±SD of 8.39±2.5. Hyperprolactinemia was found in 15% of PV patients (two female and one male) but was not reported among controls. However, this showed no statistically significant difference between serum PRL levels in PV patients and controls (P=0.4).
Our results are in agreement with those of Kavala et al. 13, who showed in their study that hyperprolactinemia was observed in 10.2% of pemphigus patients and was not observed among healthy controls (P=0.058).
In contrast to these results, Fallahzadeh et al. 14 reported that mean serum PRL levels in PV patients were significantly higher than those of controls (21.66±3.5 vs. 11.38±0.69 ng/ml, respectively, P=0.048). They found that six PV patients (25%, all women) had hyperprolactinemia, in contrast to the control group, in which no one had hyperprolactinemia.
The difference between the results of the present study and those of Fallahzadeh et al. 14 may be because of the higher severity of the disease in the latter study, as 50% of their patients showed a BSA involvement of 40% or more, whereas only 20% of patients in the present showed a similar involvement. Moreover, the method used to estimate PRL levels in the two studies was different: Fallahzadeh et al. 14 measured serum PRL level by ELISA, whereas PRL levels in this study were measured using ECLIA. ECLIAs have been found to have higher sensitivity and stability compared with ELISA.
Serum PRL levels of male patients in this study were not significantly enhanced when compared with those of controls (P=0.1), and likewise the female patients’ results were not significantly different when compared with those of controls (P=0.1).
Kavala et al. 13 reported that serum PRL levels of male patients were not significantly increased when compared with those of controls (P>0.05), whereas the levels of female patients were statistically significantly increased when compared with those of controls (P<0.05), which is similar to the results of the present study.
When comparing the relation between serum PRL levels and the type of involvement, the present statistical results showed that the mean±SD of serum PRL levels was highest in patients with mucocutaneous involvement (15.0±13.6), followed by in those with the mucosal involvement (14.3±14.3), and was the least in patients with cutaneous involvement (12.6±7.7). However, there was no statistically significant difference between the three types and PRL levels (P=0.95).
Fallahzadeh et al. 14 reported the absence of a correlation between serum PRL levels and the type of PV involvement, which is in accordance with our results.
As regards the relation between serum PRL levels and the extent of BSA involvement, a statistically highly significant correlation between the two parameters was found in the present work (P<0.001).
A high statistical significance (P<0.001) was found when serum PRL levels of each group of patients (when divided according to BSA involvement) were compared separately with the percentage of BSA involvement. Serum PRL levels in patients with BSA involvement between 20 and 39% were higher than those of patients with a BSA involvement of less than 20%, whereas serum PRL levels in patients with BSA involvement of 40% or more were higher than those of both groups.
A positive correlation between serum PRL levels and the extent of BSA involvement (P<0.01) was observed by Fallahzadeh et al. 14 in their study, which was similar to that observed in our study.
Khandpur and Reddy 15 reported a strong association between the severity of PV and serum PRL levels in a 21-year-old woman with idiopathic hyperprolactinemia and extensive mucocutaneous pemphigus. They found a positive correlation between the severity of PV, serum PRL levels, and the circulating IgG antibody titers on indirect immunofluorescence. The patient was treated by bromocriptine, which resulted in an improvement of her skin lesions. After cessation of the therapy, her PV lesions relapsed. She was retreated with bromocriptine and prednisolone, which resulted in realleviation of her disease. Thereafter, a maintenance therapy with bromocriptine was continued. It was concluded that the correlation detected between the patient’s serum PRL levels and circulating IgG antibody titers and the good therapeutic response achieved with bromocriptine therapy may give support to a causal association between PV and PRL levels.
In another case study published by Aguado et al. 5, a middle aged woman with a history of microadenoma developed mucosal as well as few cutaneous lesions of PV. Six years later, she developed breast cancer secondary to the microprolactinoma. Shortly after surgical and radiological treatment for breast cancer, she developed skin lesions suggestive of PV on the irradiated breast in addition to oral lesions. In this case, radiotherapy can induce lesions of PV, probably due to the ‘epitope spreading’ phenomenon, as the tissue damage produced by the radiotherapy causes release and exposure of a previously ‘sequestered’ antigen, leading to a secondary autoimmune response against this newly released antigen. However, it could not be ignored that the patient also had a hypophyseal PRL-producing microadenoma, which probably favored the growth of the breast neoplasm. Increases in PRL levels may be a contributing factor for the appearance of PV, as an increase in PRL levels has been associated with the onset of various autoimmune illnesses.
Finally, an unexplained finding in the present study was that about 15% of PV patients (three female patients) were hypoprolactinemic compared with 0% of controls. Similarly, in the study by Fallahzadeh et al. 14, about 16.6% of patients were hypoprolactinemic (one female and three male patients) compared with 0% of controls.
The coexistence of PV and hyperprolactinemia observed in this study and in the previous similar works may be explained on the basis of the immunostimulatory effect of PRL, leading to increased antibody production directed against the keratinocyte antigens in a genetically predisposed individual, resulting in PV. However, the source of PRL in these patients, whether from pituitary or extrapituitary, is not known yet.
Owing to the belief that the extrapituitary PRL secretion does not seem to interfere with the serum concentration of PRL and that the serum level of PRL does not correlate linearly with its autocrine and paracrine actions 16, it is suggested that the PRL initially originates from extrapituitary sites and mediates an effect on the disease process as long as the disease is mild or moderate, wherein the serum PRL level may be high, normal, or mildly increased.
In severe PV, in which serum PRL level is obviously elevated, it is suggested that pituitary PRL has a role alongside that of extrapituitary PRL. This may be explained by the belief that hyperprolactinemia cannot initiate an autoimmune disease. However, when the autoimmune disease develops and affects a large BSA, it is usually associated with a high inflammatory cell infiltration that leads to more cytokine production on one hand, and these cytokines increase the pituitary production of PRL. On the other hand, the increased lymphocytes directly secrete PRL (increased extrapituitary PRL production). In its turn, the resulting hyperprolactinemia increases disease severity.
Therefore, in the early disease process, the PRL may be normal or slightly increased but when the disease progresses, PRL may increase as well. This can be observed from the previous results, as PRL is found to be related to the extension of PV lesions (and hence disease activity) rather than to the type of involvement.
The possibility that peripheral PRL production is responsible for increased disease activity, especially in mild and moderate cases, may be suspected because of the following factors: first, some PV patients were males (males in general have less serum PRL compared with females, which is mostly produced from the pituitary gland); second, some PV patients were normoprolactinemic or hypoprolactinemic; and finally, PRL levels elevate when disease activity or severity increases because of extrapituitary PRL production by the increased lymphocytes (pituitary PRL may also increase).
| Conclusion|| |
PRL may serve as a useful biological marker of PV activity. Therefore, in severe refractory cases of PV, estimation of serum PRL levels should be carried out, as PRL-lowering drugs may serve as a useful adjuvant therapy in PV treatment.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]