Distribution of Myeloid and Plasmacytoid Dendritic Cell Subpopulations in Peripheral Blood of Hyperprolactinemic Women.

Dendritic cells (DCs) play key roles in regulating the immune response using the specialized function of processing and presenting antigens. Prolactin (PRL), a hormone produced by the pituitary gland, participates in DC maturation and function. The present study was aimed to determine the frequencies of peripheral blood DC subpopulations of myeloid DC (MDC) and plasmacytoid DC (PDC) in hyperprolactinemic (HPRL) women compared to normal healthy volunteers. This study was conducted on 70 women, including 35 HPRL patients and 35 matched healthy controls, whose PRL serum levels were in the normal range (lower than 25 ng/mL). Serum thyroid-stimulating hormone (TSH) levels were measured in both groups as an indicator of normal thyroid function. The electrochemiluminescence immunoassay method was applied to measure the serum levels of TSH and PRL. The frequencies of MDC and PDC in the peripheral blood samples of both groups were determined by flow cytometry. The mean serum PRL levels in the HPRL patients and healthy individuals were 46.41±21.96 and 13.75±11.19, respectively (p<0.0001); however TSH levels in both groups were similar and within the normal range (0.4-4.5 mIU/mL) (p=0.2). The frequencies of both MDC and PDC subpopulations in the peripheral blood of HPRL patients were significantly lower than they were in the healthy controls. However, the ratio of MDCs/PDCs in HPRL patients was not significantly different between the two groups (p=0.8). Our study revealed that an increased level of serum PRL may lead to a reduction in the number of MDC and PDC subpopulations. These results could help clarify the complex relationship between the immune system and the neuroendocrine axis and may be of potential use in understanding the pathogenesis of endocrine and immune disorders.

Prolactin, metabolic and immune parameters in naïve subjects with a first episode of psychosis.

BACKGROUND: Prolactin (Prl) is a pleiotropic hormone initially described for its regulation of lactation in mammals but later associated with metabolic and immune homeostasis, stress, inflammatory response and human behavior. Its regulation through dopamine receptors highlights its importance in psychiatry mostly because hyperprolactinemia is a common secondary side effect of dopamine antagonists. Despite its undeciphered patho-physiological mechanisms, hyperprolactinemia in naïve psychosis patients has been widely described. Its consequences might underlie the increased morbidity and early mortality found in naïve subjects as described in the general population where prolactin values have been correlated with inflammatory, immune and metabolic parameters. METHODS: We aimed to evaluate the correlation between prolactin values and other biochemical parameters (C-reactive Protein-CrP, blood cell count, lipid and hepatic profile, fasting glucose) in a cohort of first episode psychosis naïve subjects (N = 491) stratified by sex. Regression analyses with confounders were performed to evaluate the association. FINDINGS: Prl displayed significant correlations with C-Reactive Protein (CrP), Low-Density Lipoprotein (LDL), Aspartate Transaminase (AST) for females and High-Density Lipoprotein (HDL) and eosinophil count for males. However, and despite previous specific sex correlations, significant associations were described for CrP, HDL, LDL, AST and ALT without sex interaction and despite confounders such as age, Body Mass Index or smoking status. CONCLUSIONS: Our results show a specific relation of Prl with immune and metabolic parameters describing a heterogeneous pattern. Our results suggest that prolactin might underlie the excess of morbidity and early mortality in naïve patients through a specific pathway.

Evaluation of autoantibodies and immunoglobulin G subclasses in women with suspected macroprolactinemia.

BACKGROUND: Macroprolactin mostly composed of an immunoglobulin G (IgG) and a monomeric prolactin (PRL) represents the major circulating PRL form in the patients with macroprolactinemia that are usually asymptomatic and may not require treatment. In this study, we aimed to evaluate the prevalence of antithyroid and antinuclear antibodies, as well as the IgG subclass distributions in the patients suspected for macroprolactinemia. METHODS: From January to July in 2018, totally 317 patients with elevated PRL were subjected to the polyethylene glycol (PEG) precipitation assay. The patients with recovery rates of ≤60% were subjected for IgG subclass determination and autoantibody testing including thyroid peroxidase antibody (aTPO), antithyroglobulin antibody (aTG), and antinuclear antibodies (ANA). RESULTS: The higher the post-PEG PRL recovery rates, the less typical hyperprolactinemia symptoms and the higher prevalence of autoantibodies were observed. The IgG1 and IgG3 were the predominant subclasses in the PRL-IgG complexes according to the immunoprecipitation experiments. CONCLUSION: The patients with post-PEG PRL recovery rates of <40% and 40%-60% were likely to represent two distinct populations of different clinical presentations. The prevalence of autoantibodies and IgG subclasses distribution suggested their pathogenic significance in the development of macroprolactinemia.

Immunomodulating Effects Depend on Prolactin Levels in Patients with Hyperprolactinemia.

Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p<0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (>3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.

Prolactin and autoimmunity: The hormone as an inflammatory cytokine.

Nowadays, more than 80 autoimmune disorders are recognized, in which an aberrant immune response against different organs and tissues plays a crucial role. Hormonal homeostasis has great influence in achieving competent and healthy immune system function. Prolactin has a bioactive function acting as a hormone and a cytokine. It influences the immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Hyperprolactinemia has been detected in many patients with different autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, multiple sclerosis, autoimmune thyroid disease, systemic sclerosis, among others, and its believed to play a crucial role in disease pathogenesis. A direct correlation between prolactin levels and disease activity was not clear. Genetic factors may have a role in humans as in animal models. Dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, the authors attempt to provide a critical overview on the role of prolactin in the immune system, exploring its contribution to the development of autoimmune diseases.

Hyperprolactinemia is associated with a high prevalence of serum autoantibodies, high levels of inflammatory cytokines and an abnormal distribution of peripheral B-cell subsets.

PURPOSE: Hyperprolactinemia (HPRL) has been reported in many autoimmune diseases. However, the serum autoantibody profile and peripheral B-cell subset distribution in women with HPRL are largely unknown. The current study aimed to investigate the autoantibody prevalence and cytokine levels as well as to further explore the B-cell subset distribution in women with HPRL. METHODS: Sera from 202 women with HPRL and 97 healthy women were included in this study. All sera were examined for prolactin (PRL), anti-nuclear antibody (ANA), rheumatoid factor, anticardiolipin (ACL), immunoglobulin G, immunoglobulin M, complement 3, complement 4, interleukin 4 (IL-4) and interleukin 6 (IL-6). Peripheral blood was collected from 22 women with HPRL and 19 healthy women, and B-cell subsets were measured by flow cytometry. RESULTS: At least one autoantibody was found in 47 out of 202 women with HPRL compared with 9 of 97 healthy women (p < 0.001). The levels of IL-4 (p < 0.0001) and IL-6 (p < 0.0001) were significantly higher in women with HPRL than in healthy women. The percentages of naive IgD+IgM- B cells (BND cells, p < 0.0001), antibody-secreting cells (p = 0.007) and unswitched memory B cells (p = 0.004) among the total B cells from HPRL women were significantly higher than those from healthy women. CONCLUSIONS: Women with HPRL had a higher prevalence of autoantibodies, higher serum levels of IL-4 and IL-6, and more BND cells, antibody-secreting B cells and unswitched memory B cells than healthy women. These data imply that a high level of PRL is associated with autoimmune diseases.

Association of raised levels of IL-4 and anti-TPO with hyperprolactinemia.

BACKGROUND AND OBJECTIVE: The modulatory role of prolactin in autoimmune regulation is well established. Hyperprolactinemia is often associated with autoimmune disease like systemic lupus erythematosus and autoimmune thyroid diseases. The objective was to compare levels of direct and indirect autoimmune factors in different categories of hyperprolactinemia cases and predict the direction of association between hyperprolactinemia and autoimmune factors, if any. METHODS: A total of 102 hyperprolactinemia cases (>100 ng/mL serum prolactin level) were included along with 24 controls. Among 102 hyperprolactinemia cases, there were 36 idiopathic cases, 19 pituitary adenoma cases, 36 drug-induced cases, and 11 cases associated with other secondary/systemic diseases (chronic renal failure, chronic hepatic failure, etc). MEASUREMENTS: Direct autoimmune markers, IL-2, IFN-γ, IL-4, and IL-5, were measured in serum by ELISA. Indirect autoimmune markers, anti-TPO, anti-tg, anti-CCP, VDRL, platelet count, and aPTT, were measured as per laboratory-defined protocol. RESULTS: Serum levels of IL-4 and anti-TPO were significantly high in idiopathic hyperprolactinemia cases. Serum IL-4 levels were also significantly high in pituitary adenoma cases, drug-induced cases, and in cases with other secondary causes of hyperprolactinemia. Serum anti-TPO levels were also significantly high in drug-induced hyperprolactinemia cases. CONCLUSION: No significant difference in autoimmune factors is observed between macroprolactinemia and true hyperprolactinemia. Serum IL-4 and anti-TPO were high in all categories of hyperprolactinemia. This suggests a possible association of hyperprolactinemia with autoimmune conditions (high IL-4 and anti-TPO), mostly subclinical. Thus, hyperprolactinemia case with serum prolactin level >100 ng/mL may require long-term follow-up for the development of autoimmune disease in future.

Short-Term Hyperprolactinemia Reduces the Expression of Purinergic P2X7 Receptors during Allergic Inflammatory Response of the Lungs.

PURPOSE: We have previously shown that domperidone-induced short-term hyperprolactinemia reduces the lung's allergic inflammatory response in an ovalbumin antigenic challenge model. Since purinergic receptor P2X7R activity leads to proinflammatory cytokine release and is possibly related to the pathogenesis of allergic respiratory conditions, the present study was designed to investigate a possible involvement of purinergic and prolactin receptors in this phenomenon. METHODS: To induce hyperprolactinemia, domperidone was injected intraperitoneally in rats at a dose of 5.1 mg × kg-1 per day for 5 days. P2X7 expression was evaluated by lung immunohistochemistry while prolactin receptor expression in bronchoalveolar lavage leukocytes was analyzed through flow cytometry. RESULTS: Previous reports demonstrated that rats subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, especially granulocytes. Here, it is revealed that hyperprolactinemia promotes an increased expression of prolactin receptors in granulocytes. Also, increased expression of purinergic P2X7R observed in allergic animals was significantly reduced by hyperprolactinemia. CONCLUSIONS: Both purinergic and prolactin receptor expression changes occur during the anti-asthmatic effect of hyperprolactinemia.

Prolactin and Autoimmunity.

The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.

Prolactin has a pathogenic role in systemic lupus erythematosus.

Prolactin, a 23-kDa peptide hormone, is produced by the anterior pituitary gland and extrapituitary sites including the immune cells. Prolactin (PRL) participates in innate and adaptive immune response. PRL stimulates the immune cells by binding to receptor (PRL-R). Binding of PRL to its receptor activates the Janus kinase-signal transducer (JAK-STAT). Activation of these cascades results in endpoints such as immunoestimulator and immunosupressor action. Prolactin belongs to the network of immune-neuroendocrine interaction. Hyperprolactinemia has been found in patients with systemic lupus erythematosus (SLE), and new evidence has confirmed a significant correlation between serum PRL levels and disease activity. PRL participates in activation of SLE during pregnancy and in pathogenesis of lupus nephritis, neuropsychiatric, serosal, hematologic, articular, and cutaneous involvement. Hyperprolactinemia was associated with increase IgG concentrations, anti-DNA antibodies, immune complex, glomerulonephritis, and accelerated mortality in murine lupus. Bromocriptine, a dopamine analog that suppresses PRL secretion, was associated with decreased lupus activity, prolonged lifespan, and restoration of immune competence in experimental model. In clinical trials, bromocriptine and derivative drugs showed beneficial therapeutic effect in treating human lupus, including pregnancy. Taken together, clinical and experimental results leave little doubt that PRL indeed contributes to the pathogenesis and clinical expression of SLE.

Maternal flaxseed oil intake during lactation changes body fat, inflammatory markers and glucose homeostasis in the adult progeny: role of gender dimorphism.

We evaluated maternal flaxseed oil intake during lactation on body composition, lipid profile, glucose homeostasis and adipose tissue inflammation in male and female progeny at adulthood. Lactating rats were divided into the following: control 7% soybean oil (C), hyper 19% soybean oil (HS) and hyper 17% flaxseed oil+2% soybean oil (HF). Weaned pups received a standard diet. Offspring were killed in PN180. Male HF presented higher visceral adipose tissue (VAT) and triacylglycerol, and female HF showed insulin resistance. Both male and female HF had hyperleptinemia, and only male HF had hyperprolactinemia. In VAT, male HF presented lower PPAR-γ expressions and higher TNF-α, IL-6, IL-1ß and IL-10 expressions; in subcutaneous adipose tissue (SAT), they presented lower PPAR-γ and TNF-α expressions. Female HF presented higher leptin, as well as lower adiponectin, TNF-α, IL-6 and IL-1ß expressions in VAT and lower TNF-α in SAT. Flaxseed oil during lactation leads to gender-specific effects with more adiposity and dyslipidemia in male and insulin resistance in female. Higher prolactin and inflammatory cytokines in male could play a role in these gender differences. We suggest that the use of flaxseed oil during lactation increases metabolic syndrome risk in the adult progeny.

Short-term hyperprolactinemia decreases allergic inflammatory response of the lungs.

AIMS: Prolactin is a major immunomodulator. The present study evaluated the effects of short-term hyperprolactinemia induced by domperidone before ovalbumin antigenic challenge on the lung's allergic inflammatory response. MAIN METHODS: To induce hyperprolactinemia, domperidone was injected in rats at a dose of 5.1mg·kg(-1) per day, i.p., for 5days from 10th to 14th day after OVA immunization. Total and differential leukocyte counts from bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood were analyzed. The percentages of mucus and collagen production were evaluated. Levels of corticosterone and prolactin in serum, interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor α (TNF-α) in lung explants supernatants were measured and interferon gamma (IFN-γ) in bronchiolar lavage cells suspensions (BAL) was measured. KEY FINDINGS: The rats that were subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, cellularity decrease in femoral marrow lavage fluid, a lower percentage of mucus, and an increase in lung IL-4, IL-6, IL-10, TNF-α and IFN-γ expression. SIGNIFICANCE: Hyperprolactinemia induced before antigenic challenge decreased allergic lung inflammation. These data suggest that prolactin may play a role in the pathophysiology of asthma. The present study demonstrates a prospective beneficial side effect of domperidone for asthmatic patients.

Urine oligosaccharide pattern in patients with hyperprolactinaemia.

Free milk-type oligosaccharides are produced during pregnancy and lactation and may have an impact on several cells in the immune system. Our aim was to investigate if patients with isolated hyperprolactinaemia, not related to pregnancy, also have increased synthesis and urinary excretion of milk-type oligosaccharides and to compare the excretion pattern with that found during pregnancy. Urine samples were collected as morning sample from 18 patients with hyperprolactinaemia, 13 healthy controls with normal prolactin levels and four pregnant women. After purification, lactose and free oligosaccharides were analysed and quantified by high-performance anion-exchange chromatography with pulsed amperometric detection. The identity of peaks was confirmed by exoglycosidase treatment and comparison with oligosaccharide standards. Prolactin was measured in serum collected between 09 and 11 a.m. by a standardized immunochemical method. Patients with hyperprolactinaemia had higher urinary excretion of lactose than normoprolactinemic controls and urinary lactose correlated positively to prolactin levels (r = 0.51, p < 0.05). Increased levels of the fucosylated oligosaccharides 2-fucosyl lactose and lacto-di-fucotetraose were found in urine from three and two patients, respectively. The acidic oligosaccharide 3-sialyl lactose was found in high amount in urine from two patients with prolactin of >10,000 mU/l. However, pregnant women in their third trimester had the highest concentration of all these oligosaccharides and excretion increased during pregnancy. This study is first to show that both lactose and certain fucosylated and sialylated milk-type oligosaccharides are increased in some patients with hyperprolactinaemia. It remains to elucidate the functional importance of these findings.

Serum macroprolactin levels in pregnancy and association with thyroid autoimmunity.

BACGROUND: To assess the contribution of macroprolactin to high serum prolactin levels and their association with thyroid status and thyroid autoimmunity during pregnancy. METHODS: 138 pregnant women who suspected of having thyroid dysfunction were studied and divided into three groups according to the thyroid status; group 1; euthyroidism (n 40), group 2; hypothyroidism (n 54), and group 3; hyperthyroid (n 44). Polyethylene glycol (PEG) precipitation method was used for detection of macroprolactin. A percentage recovery of 40 % or less is considered as macroprolactinemia. If macroprolactin was negative, the percentage of monomeric prolactin recovery (monoPRL %) after PEG precipitation was used for comparison between the groups. RESULTS: Macroprolactinemia was found in two patients (1.4 %) one from hypothyroid and other from euthyroid group. Basal prolactin levels in these patients were 400 and 403 ng/mL respectively. Referring to all patients, there was no correlation between PRL, macroPRL or monoPRL % with thyroid hormone status and also with the serum levels of thyroid antibodies (p > 0.05). A positive correlation was observed between the serum levels of PRL with TSH (p = 0.014 and r = 0.219), while a negative correlation was found with FT4 (p = 0.011 and r = -0.227). CONCLUSIONS: Despite the fact that serum prolactin levels were found to be high during pregnancy, the contribution of macroprolactin was found to be insignificant in our study. Unlike other auto immune diseases, we could not find any relationship between thyroid autoimmunity and PRL, macroPRL or monoPRL %. These results confirmed that measured prolactin was quite homogeneous during pregnancy.

Importance of macroprolactinemia in hyperprolactinemia.

Macroprolactin is an antigen-antibody complex of higher molecular mass than prolactin (>150kDa), consisting of monomeric prolactin and immunoglobulin G. The term 'macroprolactinemia' is used when the concentration of macroprolactin exceeds 60% of the total serum prolactin concentration determined by polyethylene glycol precipitation. The gold standard technique for the diagnosis of macroprolactinemia is gel filtration chromatography. The prevalence of macroprolactinemia in hyperprolactinemic populations varies between 15% and 35%. Although the pathogenesis of these antibodies is not clear, it is possible that changes in the pituitary prolactin molecule represent increased antigenicity to the immune system, leading to the production of anti-prolactin antibodies. Mild hyperprolactinemia usually occurs because macroprolactin is not cleared readily from the circulation due to its higher molecular weight. Moreover, the hypothalamic negative feedback mechanism for autoantibody-bound prolactin is inactive because macroprolactin cannot access the hypothalamus, resulting in hyperprolactinemia. Reduced in-vivo bioactivity of macroprolactin may be the reason for the lack of hyperprolactinemic symptoms. It also seems that anti-prolactin autoantibodies may compete with prolactin molecules for receptor binding, resulting in low bioactivity. Additionally, the large molecular size of macroprolactin confined in the intravascular compartment prevents its passage through the capillary endothelium to the target cells, which may be the reason for the lack of symptoms. Macroprolactinemia is considered to be a benign clinical condition in patients with normal concentrations of bioactive monomeric prolactin, with a lack, or low incidence, of hyperprolactinemic symptoms and negative pituitary imaging. In such cases with resistance to anti-prolactinaemic drugs, no pharmacological treatment, diagnostic investigations or prolonged follow-up are required. However, macroprolactinemia may also occur in patients with conventional symptoms of hyperprolactinemia who cannot be differentiated from patients with true hyperprolactinemia. These symptoms are mainly attributed to excess levels of monomeric prolactin, and this is of concern. The diagnosis of macroprolactinemia is misleading and inappropriate. A multitude of physiological, pharmacological and pathological causes, including stress, prolactinomas, hypothyroidism, renal and hepatic failure, intercostal nerve stimulation and polycystic ovary disease, can contribute to increased levels of monomeric prolactin. It is important for patients with elevated monomeric prolactin levels to undergo routine evaluation to identify the exact pathological state and introduce adequate treatment, regardless of the presence of macroprolactin. In addition, macroprolactinemia occasionally occurs due to macroprolactin associated with pituitary adenomas, with biological activity of macroprolactin comparable with that of monomeric prolactin. In cases when excess macroprolactin occurs with clinical manifestations of hyperprolactinemia, macroprolactinemia should be regarded as a pathological biochemical variant of hyperprolactinemia. An individualized approach to the management of such patients with macroprolactinemia may be necessary, and pituitary imaging, dopamine treatment and prolonged follow-up should be applied.

Thyroid autoimmunity in patients with hyperprolactinemia: an observational study.

OBJECTIVE: To establish whether there is a relationship between hyperprolactinemia and primary thyroid disorders, focusing on patients with autoimmune features. MATERIALS AND METHODS: The medical records of 100 patients with hyperprolactinemia (HPRL) were retrospectively examined. Records of thyroid ultrasonography (USG), basal serum levels of thyroid stimulating hormone, circulating free thyroxine, free triiodothyronine, antithyroglobulin (anti-Tg), and antithyroperoxidase (anti-TPO) antibodies were analyzed. In 100 control subjects, matched by age and gender with HPRL patients, thyroid USG, thyroid function tests (TFTs), and autoantibody panel were obtained. RESULTS: The median PRL in patients was 93 ng/mL (range: 37-470). Twenty-five patients (25%) and 22 controls (22%) had positive anti-Tg and/or anti-TPO titers (P = 0.739). The median serum PRL was 98 (37-470) ng/mL in patients with positive thyroid autoantibodies, and 92 (40-470) ng/mL in patients who were negative (P = 0.975). Among the individuals with autoantibody positivity TFTs abnormalities were more frequent in HPRL patients (60%, out of 25 patients, 14 with subclinical hypothyroidism and one with hyperthyroidism) than in controls (9.1%, out of 22 patients, 2 with subclinical hyperthyroidism) (P < 0.001). Twenty-seven patients with HPRL and 31 controls had goiter (27 vs. 31%, P = 0.437). Forty-six patients (46%) and 50 (50%) controls had one or more of the features of thyroid disorder, which were goiter, positive thyroid autoantibody, and thyroid function abnormality (P = 0.888). CONCLUSION: HPRL may be associated with more severe thyroid dysfunction in patients with thyroid autoimmunity.

Thyroid autoimmunity in patients with hyperprolactinemia: an observational study / Autoimunidade tireoidiana em pacientes com hiperprolactinemia: um estudo observacional

Objective : To establish whether there is a relationship between hyperprolactinemia and primary thyroid disorders, focusing on patients with autoimmune features. Materials and methods : The medical records of 100 patients with hyperprolactinemia (HPRL) were retrospectively examined. Records of thyroid ultrasonography (USG), basal serum levels of thyroid stimulating hormone, circulating free thyroxine, free triiodothyronine, antithyroglobulin (anti-Tg), and antithyroperoxidase (anti-TPO) antibodies were analyzed. In 100 control subjects, matched by age and gender with HPRL patients, thyroid USG, thyroid function tests (TFTs), and autoantibody panel were obtained. Results : The median PRL in patients was 93 ng/mL (range: 37-470). Twenty-five patients (25%) and 22 controls (22%) had positive anti-Tg and/or anti-TPO titers (P = 0.739). The median serum PRL was 98 (37-470) ng/mL in patients with positive thyroid autoantibodies, and 92 (40-470) ng/mL in patients who were negative (P = 0.975). Among the individuals with autoantibody positivity TFTs abnormalities were more frequent in HPRL patients (60%, out of 25 patients, 14 with subclinical hypothyroidism and one with hyperthyroidism) than in controls (9.1%, out of 22 patients, 2 with subclinical hyperthyroidism) (P < 0.001). Twenty-seven patients with HPRL and 31 controls had goiter (27 vs. 31%, P = 0.437). Forty-six patients (46%) and 50 (50%) controls had one or more of the features of thyroid disorder, which were goiter, positive thyroid autoantibody, and thyroid function abnormality (P = 0.888). Conclusion : HPRL may be associated with more severe thyroid dysfunction in patients with thyroid autoimmunity. .

Objetivo : Verificar se existe uma relação entre a hiperprolactinemia e distúrbios primários da tireoide, focando em pacientes com características autoimunes. Materiais e métodos : Os prontuários de 100 pacientes com hiperprolactinemia (HPRL) foram examinados retrospectivamente. Foram analisados registros de ultrassonografia da tireoide (USG), níveis séricos basais de hormônio tireoestimulante, tiroxina livre, triiodotironina livre e anticorpos antitireoglobulina (anti-Tg) e antitireoperoxidase (anti-TPO). Foram obtidos de 100 controles, pareados por idade e sexo com pacientes com HPRL, USG, testes de função da tireoide (TFTs) e painel de autoanticorpos. Resultados : A média de PRL em pacientes foi de 93 ng/mL (variação: 37-470). Vinte e cinco pacientes (25%) e 22 controles (22%) foram positivos para títulos de anti-Tg e/ou anti-TPO (P = 0,739). A mediana de PRL sérica foi de 98 (37-470) ng/mL em pacientes positivos para autoanticorpos tiroidianos e 92 (40-470) ng/mL em pacientes negativos (P = 0,975). Entre os indivíduos positivos para autoanticorpos, as anormalidades da TFTs foram mais frequentes em pacientes HPRL (60%; de 25 pacientes, 14 com hipotireoidismo subclínico e um com hipertireoidismo) do que nos controles (9,1%; de 22 pacientes, 2 com hipertireoidismo subclínico) (P < 0,001). Vinte e sete pacientes com HPRL e 31 controles apresentavam bócio (27 contra 31%; P = 0,437). Quarenta e seis pacientes (46%) e 50 (50%) controles tiveram uma ou mais das características de problemas de tireoide, como bócio, autoanticorpos antitireoide e anormalidades da função tiroidiana (P = 0,888). Conclusão : A HPRL pode estar associada à disfunção da tireoide mais grave em pacientes com autoimunidade contra a tireoide. .

Prolactin promotes normal liver growth, survival, and regeneration in rodents: effects on hepatic IL-6, suppressor of cytokine signaling-3, and angiogenesis.

Prolactin (PRL) is a potent liver mitogen and proangiogenic hormone. Here, we used hyperprolactinemic rats and PRL receptor-null mice (PRLR(-/-)) to study the effect of PRL on liver growth and angiogenesis before and after partial hepatectomy (PH). Liver-to-body weight ratio (LBW), hepatocyte and sinusoidal endothelial cell (SEC) proliferation, and hepatic expression of VEGF were measured before and after PH in hyperprolactinemic rats, generated by placing two anterior pituitary glands (AP) under the kidney capsule. Also, LBW and hepatic expression of IL-6, as well as suppressor of cytokine signaling-3 (SOCS-3), were evaluated in wild-type and PRLR(-/-) mice before and after PH. Hyperprolactinemia increased the LBW, the proliferation of hepatocytes and SECs, and VEGF hepatic expression. Also, liver regeneration was increased in AP-grafted rats and was accompanied by elevated hepatocyte and SEC proliferation, and VEGF expression compared with nongrafted controls. Lowering circulating PRL levels with CB-154, an inhibitor of AP PRL secretion, prevented AP-induced stimulation of liver growth. Relative to wild-type animals, PRLR(-/-) mice had smaller livers, and soon after PH, they displayed an approximately twofold increased mortality and elevated and reduced hepatic IL-6 and SOCS-3 expression, respectively. However, liver regeneration was improved in surviving PRLR(-/-) mice. PRL stimulates normal liver growth, promotes survival, and regulates liver regeneration by mechanisms that may include hepatic downregulation of IL-6 and upregulation of SOCS-3, increased hepatocyte proliferation, and angiogenesis. PRL contributes to physiological liver growth and has potential clinical utility for ensuring survival and regulating liver mass in diseases, injuries, or surgery of the liver.

Prolactin rescues and primes autoreactive B cells directly and indirectly through dendritic cells in B6.Sle3 mice.

The lupus susceptibility interval Sle3/5 confers responsiveness to prolactin in C57BL/6 (B6) mice and hyperprolactinaemia induces a lupus-like phenotype in B6.Sel3/5 mice. In this study, the immunostimulatory effects of prolactin in B6 mice containing the Sle3 portion of the Sel3/5 interval (B6.Sle3 mice) were dissected. Because of the Sle3 interval's involvement in activation of myeloid cells, the effect of dendritic cells (DCs) from prolactin-treated B6.Sle3 mice on the phenotype of B6 mice was also evaluated. B cells from prolactin-treated B6 and B6.Sle3 mice and from B6 recipients of prolactin-modulated DCs from B6.Sle3 mice were tested for DNA-reactivity and resistance to B cell receptor (BCR)-mediated apoptosis. The expression of co-stimulatory molecules on lymphocytes and myeloid cells was also evaluated. In prolactin-treated B6.Sle3 mice, transitional type 2 B cells increased while type 1 B cells decreased as a consequence of prolactin-induced resistance to BCR-mediated apoptosis leading to the survival of DNA-reactive B cells. Follicular B cells from prolactin-treated mice expressed increased levels of CD40, B7·2 and IA(b), and DCs and monocytes had higher levels of CD44 and B7·2 than placebo-treated mice. Adoptive transfer of DCs from prolactin-treated B6.Sle3 mice to B6 recipients demonstrated the intrinsic ability of prolactin-modulated DCs to induce a development of lupus-like characteristics in B6 mice. Based on these results, prolactin accelerates the breakdown of immune tolerance in B6.Sle3 mice by promoting the survival, maturation and activation of autoreactive B cells, DCs and macrophages.

Prolactin levels correlate with abnormal B cell maturation in MRL and MRL/lpr mouse models of systemic lupus erythematosus-like disease.

Prolactin (PRL) plays an important role in modulating the immune response. In B cells, PRL enhances antibody production, including antibodies with self-specificity. In this study, our aims were to determine the level of PRL receptor expression during bone-marrow B-cell development and to assess whether the presence of high PRL serum concentrations influences absolute numbers of developing populations and disease outcome in lupus-prone murine models. We observed that the PRL-receptor is expressed in early bone-marrow B-cell; the expression in lupus-prone mice, which had the highest level of expression in pro-B cells and immature cells, differed from that in wild-type mice. These expression levels did not significantly change in response to hyperprolactinemia; however, populations of pro-B and immature cells from lupus-prone strains showed a decrease in the absolute numbers of cells with high PRL-receptor expression in response to PRL. Because immature self-reactive B cells are constantly being eliminated, we assessed the expression of survival factor BIRC5, which is more highly expressed in both pro-B and immature B-cells in response to PRL and correlates with the onset of disease. These results identify an important role of PRL in the early stages of the B-cell maturation process: PRL may promote the survival of self-reactive clones.