Circulating prolactin levels and the effect of dopaminergic agonists in systemic lupus erythematosus: a systematic review and meta-analysis

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We searched PubMed, Scopus, Web of Science, Cochrane, Embase, and Google Scholar for case-control and cross-sectional studies investigating circulating PRL levels in subjects with SLE and/or its correlation with disease activity, and clinical trials examining the effect of dopaminergic agonists on SLE activity assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. Forty-five studies addressing circulating PRL levels in SLE met our inclusion criteria. SLE was associated with an increased odds of hyperprolactinemia (OR 11.69, 95%CI 5.64–24.22) and circulating PRL levels were significantly higher in subjects with SLE than in controls (standardized mean difference of 1.96, 95%CI 1.27–2.65). Circulating PRL was positively correlated with SLE activity assessed by the SLEDAI (correlation coefficient 0.38, 95% CI 0.26–0.48). Two randomized clinical trials with bromocriptine and three prospective open-label trials with quinagolide reported that treatment with dopaminergic agonists was associated with reduced frequency of disease flare and decreased SLEDAI score. Circulating PRL levels were higher in subjects with SLE than in healthy controls and are significantly associated with disease activity. In addition, treatment with the dopaminergic agonists bromocriptine and quinagolide reduced SLE disease activity and may be a beneficial adjuvant therapy for the disease. This review was registered in PROSPERO (CRD42021237156). Health sciences/Endocrinology Health sciences/Rheumatology systemic lupus erythematosus prolactin disease activity dopaminergic agonists bromocriptine quinagolide Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Systemic lupus erythematosus (SLE) is a challenging autoimmune disease characterized by diverse clinical manifestations virtually affecting any organ system and with varied severity, ranging from mild and restricted skin involvement to life-threatening vital organ impairment 1 . The mechanisms underlying immune dysfunction in SLE are complex and involve multiple molecular pathways 2 . Significant advances in the understanding of SLE pathogenesis over the last decade have highlighted that various genetic, epigenetic, environmental, and hormonal factors interact to alter immune function and lead to autoimmunity and inflammation 2 . Similarly to other autoimmune diseases, SLE is significantly more prevalent in women, with a female-to-male ratio ranging from 8:1 to 15:1 3,4 . The latter difference is more pronounced during reproductive age, and SLE activity indicated by disease flares is well-known to increase in pregnancy 5 and with estrogen-containing therapies 6 . The latter aspects suggest that hormonal influences such as sex steroids and prolactin may be involved in its pathophysiology and clinical course. Prolactin (PRL) is a polypeptide encoded by the PRL gene on chromosome 6 in humans. It is synthesized and secreted by lactotroph cells in the anterior hypophysis and by a myriad of extra-hypophysial sites, such as lymphocytes, ovary, prostate, and adipose tissue, in addition to having many different targets 7 . PRL is well-known for its critical role in stimulating the proliferation and differentiation of mammary cells required for lactation. There is also increasing evidence that PRL has pleiotropic functions, affecting metabolic homeostasis, bone physiology, skin and hair follicles, maternal care, adrenal function, immunity, and inflammatory response 7 , 8 . The role of PRL in modulating both innate and acquired immunity raises the question of whether it could be involved in the pathogenesis of autoimmune diseases 9 , 10 . Data from preclinical and clinical research indicate that PRL may affect immune function and the clinical phenotype in SLE. It has been shown to impact autoantigen presentation, interfere with the activity of regulatory T cells, and affect B cell tolerance, the production of cytokines, and neutrophil, macrophage, and dendritic cell function 9 . Moreover, hyperprolactinemia is reported in 20 to 30% of subjects with SLE 11 , and serum PRL levels were associated with the occurrence of neuropsychiatric, renal, cutaneous, and articular manifestations 12 , 13 , in addition to anti-dsDNA positivity and higher scores of disease activity 14 , 15 . However, the mechanisms underlying higher prolactin levels in SLE are not clear, but there is evidence indicating multiple sources, such as increased production by lymphocytes, the stimulatory action of inflammatory cytokines on lactotrophs to increase pituitary PRL secretion, and genetic factors leading to upregulated PRL gene expression 9 . It is noteworthy, however, that the association between circulating PRL levels and SLE activity is not consistent between different studies. This may be accounted for the heterogeneity in study participants between different studies and the different methods to determine serum prolactin levels or disease activity 9 , 16 , 17 . In this setting, we conducted a systematic review and meta-analysis to investigate circulating PRL levels in subjects with SLE compared with healthy controls and examine the correlation between PRL levels and SLE activity. In addition, as a proof of concept for the biologically plausible role of PRL in modulating SLE activity, we conducted a systematic review of clinical trials to investigate the effect of dopamine agonists on SLE activity. Materials and methods Protocol and registration This systematic review and meta-analysis was registered in the PROSPERO (International Prospective Register of Systematic Reviews) database (CRD42021237156). We followed the recommendations from the Preferred Reporting Items for Systematic Review and Meta-Analysis (Appendix A) 18 and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines 19 . Search strategy, study selection, and data extraction The study questions of the review were created using the PECOS/PICOS acronym (population, exposure/intervention, comparison, outcome, and type of study). For the first review question, whether circulating PRL levels were higher in subjects with SLE compared with healthy controls and were correlated with SLE activity, P was ‘children, men, and nonpregnant and nonlactating women with SLE,’ E was ‘circulating PRL concentration,’ C was ‘healthy subjects’ for case-control studies, O was ‘disease activity assessed by any score,’ and S was ‘cross-sectional or case-control studies.’ Therefore, we searched for studies (i) comparing circulating PRL concentration between subjects with SLE and healthy controls, (ii) comparing the frequency of hyperprolactinemia between subjects with SLE and healthy controls, and/or (iii) addressing the association between circulating PRL levels and SLE activity assessed by a validated score. For the second review question, whether treatment with dopaminergic agonists affected SLE activity, P was ‘subjects with SLE,’ I was ‘dopamine agonists,’ C was ‘subjects with SLE not treated with dopamine agonists,’ O was ‘disease activity assessed by any score,’ and S was ‘clinical trials or case-control studies.’ The inclusion criteria were clinical trials or case-control studies examining the effect of any dopamine agonist on indicators of SLE activity. Reviews, case reports, case series, book chapters, and conference abstracts were excluded. Studies involving pregnant women were also excluded. We searched PubMed, Scopus, Web of Science, Cochrane, Embase, and Google Scholar from inception to July 27, 2023, using search terms related to the population (SLE), the exposure (prolactin) or intervention (dopaminergic agonists), and the outcome (disease activity), considering studies published in English, Portuguese, or Spanish. Only the first 100 retrieved records from Google Scholar were considered. The search strategy is presented in Appendices B and C. We also conducted manual searches across reference lists of the included studies. A reference management software (Endnote version 9) was used to collect the references and exclude duplicate studies. Study selection was conducted in two phases. First, two reviewers (A.A.S. e L.F.C.) independently screened the titles and abstracts to select eligible studies. Secondly, the same reviewers independently read the full-text version of the selected studies and applied the inclusion and exclusion criteria. In each phase, disagreements between the two reviewers were resolved by discussion with a third reviewer (A.A.A.). For the first review question, the authors, year of publication, country, study design, sample size, age range, sex, method to determine circulating PRL levels, method for SLE activity assessment, and main findings were extracted from the studies. The main findings were extracted considering the following outcomes: (i) hyperprolactinemia rate in subjects with SLE and healthy controls, (ii) circulating PRL levels in subjects with SLE and healthy controls, (iii) hyperprolactinemia rate in subjects with active versus inactive SLE, (iv) circulating PRL levels in subjects with active versus inactive SLE, and (v) the correlation between circulating PRL levels in subjects with SLE and disease activity. For the second review question, the authors, year of publication, sample size, age range, sex, type of dopamine agonist, method for SLE activity assessment, main findings, and study design were extracted from the included studies. Risk of bias between studies The risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist 20 for cross-sectional (Appendix D) and case-control studies (Appendix E), for the first review question, and quasi-experimental trials (Appendix F) and randomized clinical trials (Appendix G), for the second review question. The assessment was independently conducted by two reviewers (A.A.S. and L.F.C.) following agreement on scoring decisions. Any disagreement was resolved by discussion with a third reviewer (A.A.A.). A high risk of bias was considered when the study reached 49% or less of the score ‘yes,’ a moderate risk of bias when it reached 50 to 69% of the score ‘yes,’ and a low risk of bias when it reached 70% or more of the score ‘yes’. Results of individual studies The data extracted from individual studies were presented in a table format, with their main findings described. Synthesis of results (meta-analysis) We pooled the following data from individual studies, using random-effect meta-analysis: (i) hyperprolactinemia rate in subjects with SLE and healthy controls, (ii) circulating PRL levels in subjects with SLE and healthy controls, (iii) hyperprolactinemia rate in subjects with active or inactive SLE, and (iv) the correlation between circulating PRL levels in subjects with SLE and disease activity. Data on hyperprolactinemia rate in subjects with SLE and healthy controls were summarized as odds ratio with 95% confidence interval (95%CI), and data on circulating PRL levels in subjects with SLE and healthy controls were reported standardized mean difference with 95% confidence interval. Circulating PRL levels assessed in mIU/L were converted into ng/mL dividing the results by 21 15 . We did not pool data on circulating PRL levels in subjects with active and inactive SLE since most studies only described mean or median values without the error, and some studies did not report the number of subjects with active or inactive disease. To assess the correlation between SLEDAI and serum PRL, a meta-analysis of the Pearson correlation coefficient extracted from each study was performed using the random-effects model 21 . If study values for the Pearson correlation coefficient ( r ) were not available, the Spearman correlation ( rs ) coefficient were used to estimate r values using the following formula: r = 2 × sin( rs ×p/6) 22 . Correlation coefficient values were converted by Fisher's r-to-z transformation to obtain approximately normally distributed z values and the related 95% confidence interval. Statistical heterogeneity across studies was examined using the I 2 statistic, and publication bias (small-study effect) was assessed by examining the funnel plot. Statistical significance was considered when at p < 0.05. The analyses were conducted using RevMan software 5.4 and STATA 16.0 software package. Results For the first review question, whether circulating PRL levels were higher in subjects with SLE compared with healthy controls and were correlated with SLE activity, our search retrieved 220 studies, of which 55 were selected for full-text assessment. Fifty-five studies met our inclusion criteria, and ten were excluded (Fig. 1 , Appendix H). For the second review question, whether treatment with dopaminergic agonists affected SLE activity, we identified 468 studies, and eight were selected for full-text assessment (Fig. 2 ). Three studies were excluded: one was excluded because it involved dopamine agonist administration during pregnancy 23 , and two were excluded because they did not report SLEDAI scores following dopamine agonist treatment 24 , 25 . Characteristics of studies examining circulating prolactin concentration in systemic lupus erythematosus Seventeen studies were conducted in Asia 15 , 26 – 41 , 12 in America 12 , 42 – 52 , 11 in Europe 13 , 53 – 62 , and five in Africa 63 – 67 . Fifteen studies had a cross-sectional design and examined the association between circulating PRL levels and SLE activity, whereas 30 were case-control studies comparing circulating PRL levels between subjects with SLE and healthy controls and/or investigating the association between circulating PRL levels and SLE activity. Sample sizes ranged from 19 to 259 subjects, and most studies described as exclusion criteria conditions affecting circulating PRL levels, such as pregnancy, lactation, renal and hepatic failure, or drugs. The methods to determine circulating PRL concentration varied between studies, and most presented total PRL levels; three also reported free PRL levels 12 , 51 , 53 . SLE activity was most frequently assessed by the SLE Disease Activity Index (SLEDAI) score and less frequently by the European Consensus Lupus Activity Measure (ECLAM) index 57 , 61 , the Systemic Lupus Activity Measure (SLAM) index 37 , 64 , Duke Severity of Illness (DUSOI) score 30 , or the combination of signs, symptoms, and serologic markers 54 . Study characteristics are presented in Table 1 . Table 1 Characteristics of included studies (n = 45). Authors, year Country Study design Population PRL assessment Serum prolactin PRL and disease activity Conclusion Lavalle et al., 1987 Mexico Case-control SLE n = 8 (male, mean 28.1 y, range 19–39 y) Controls n = 11 (male, mean 28.5 y, range 25–40 y) Exclusion criteria: active SLE, renal/liver failure, hypothyroidism, pituitary adenoma RIA Hyperprolactinemia (assay cutoff NR) SLE: 7/8 Controls: 0/11 Serum PRL (ng/mL; mean ± SD) SLE: 16 ± 3 Controls: 4.3 ± 0.5 p < 0.01 - Serum PRL levels were higher in subjects with SLE compared to healthy controls Folomeev et al., 1990 Russia Case control SLE n = 29 (male) Controls n = 10 (male) Exclusion criteria: NR RIA Serum PRL (mU/mL; mean ± SEM) SLE: 358.10 ± 67.35 Controls: 135.75 ± 10.319 p < 0.05 - Serum PRL levels were higher in subjects with SLE compared to healthy controls Jara et al., 1992 US Case-control SLE n = 45 Healthy controls n = 28 (12 male, 16 female; range 20–65 y) Exclusion criteria: NR RIA Hyperprolactinemia (> 20 ng/mL): SLE: 10/45 Control: 0/28 Serum PRL (ng/mL; mean, range) SLE: 17.2, 3.6–188 Controls: 8.4, 2.5–17.5 SLEDAI Correlation PRL and SLEDAI r p = 0.369 p = 0.012 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Sequeira et al., 1993 UK Case-control SLE n = 14 (male; mean 36 ± 12.2 y, range 22–67 y) Controls n = 17 (male; mean 31 ± 4.0 y, range 27–40 y) Exclusion criteria: hypogonadism, previous therapy with cyclophosphamide ETA Hyperprolactinemia (> 360 mIU/L) SLE: 1/14 Controls: 0/17 Serum PRL (mIU/L; mean ± SD) SLE: 171 ± 107 Controls: 167 ± 161 p > 0.05 - Serum PRL levels were not higher in subjects with SLE compared to healthy controls Buskila et al., 1996 Israel Cross-sectional SLE n = 63 (4 male, 59 female; mean 31.6 y, range 16–68 y) Exclusion criteria: pregnancy, lactation, abnormal thyroid function, abnormal liver function, renal failure, drugs interfering with PRL serum levels IRMA - SLEDAI Correlation PRL and SLEDAI r p = -0.186 p > 0.05 Serum PRL levels were not correlated with disease activity El-Garf et al., 1996 Egypt Case-control SLE n = 33 (5 male, 28 female; mean 10.9 y, range 6–13 y) Controls n = 20 (4 male, 16 female; mean 11.6 y, range 7–13 y) Exclusion criteria: sellar abnormalities, visual field and fundi abnormalities, drugs interfering with PRL serum levels IRMA Hyperprolactinemia (> 25.53 ng/mL) SLE: 3/33 Controls: 0/20 Serum PRL (ng/mL; mean ± SD) SLE: 14.42 ± 7.5 Controls: 12.69 ± 6.42 p > 0.05 SLAM Correlation PRL and SLEDAI r p = 0.089 p > 0.05 Serum PRL levels were not higher in subjects with SLE compared to healthy controls and were not correlated with disease activity Ostendorf et al., 1996 Germany Cross-sectional n = 182 (14 male, 168 female; mean 41 y, range 16–72 y) Exclusion criteria: NR (none of the included subjects were taking drugs interfering with PRL serum levels) ELISA Hyperprolactinemia (> 15 ng/mL for male and > 20 ng/mL for female): 4/182 DAI Correlation PRL and SLEDAI r = NR p > 0.05 Serum PRL levels were not correlated with disease activity Rovensky et al., 1997 Slovakia Cross-sectional SLE n = 35 (4 male, 31 female, mean 45 ± 2 y) Exclusion criteria: pregnancy, lactation, hypothyroidism RIA - ECLAM Correlation PRL and SLEDAI r s = 0.201 p = 0.24 Serum PRL levels were not correlated with disease activity Ferreira et al., 1998 Portugal Case-control SLE n = 24 (1 male, 23 female; mean 42.5 ± 14.0 y, range 17–65 y) Controls n = 15 (1 male, 14 female; mean 39.9 ± 11.2 y, range 27–64 y) Exclusion criteria: NR MEIA Hyperprolactinemia (> 20 ng/mL): SLE: 9/24 Control: 2/15 Serum PRL (ng/mL; mean ± SD) SLE: 19.3 ± 9.2 Controls: 10.2 ± 5.5 p 0.05 Serum PRL levels were higher in subjects with SLE compared to healthy controls but were not correlated with disease activity Jimena et al., 1998 UK Case-control SLE n = 36 (female; 32.3 ± 8.5 y) Healthy controls n = 20 (female; mean 32.2 ± 9.3 y) Exclusion criteria: pregnancy, lactation, renal/hepatic failure, drugs interfering with serum PRL levels RIA Hyperprolactinemia (> 20 ng/mL) SLE: 10/36 Controls: 0/20 Serum PRL (ng/mL; mean ± SD, and range) SLE: 17.1 ± 12.9, 4–36 Controls: 9.9 ± 3.5, 5-16.6 p 10) Serum PRL according to SLEDAI (ng/mL mean ± SD, and range) ≤ 10: 14.8 ± 6.9 > 10: 21.1 ± 4.8 p = 0.09 Correlation PRL and SLEDAI r p = 0.049 p = 0.52 Serum PRL levels were higher in subjects with SLE compared to healthy controls but were not correlated with disease activity Mok et al., 1998 Hong Kong Case-control SLE n = 31 (male; mean 39.0 ± 2.7 y, range 18–71 y) Controls n = 31 (male; mean 39.3 ± 2.4 y, range 20–71 y) Exclusion criteria: prolactinoma, renal failure, chest wall lesions, hypothyroidism, drugs interfering with serum RIA Serum PRL (mIU/L, mean ± SD) SLE 230 ± 14 Controls: 194 ± 17 p = 0.06 SLEDAI (> 5) Serum PRL according to SLEDAI (IU/mL mean) ≤ 4: 227 > 5: 234 p = 0.63 Correlation PRL and SLEDAI r s = 0.24 p = 0.09 Serum PRL levels were not higher in subjects with SLE compared to healthy controls and were not correlated with disease activity Chang et al., 1999 China Case-control SLE n = 16 (male, mean 26 ± 9 y, range 19–46 y) Controls n = 20 (male, mean 30 ± 4 y) Exclusion criteria: NR RIA Serum PRL (ng/mL) SLE: 17.6 ± 10.6 Controls: 6.6 ± 2.8 p = 0.012 - Serum PRL levels were higher in subjects with SLE compared to healthy controls Mok et al., 2000 Hong Kong Case-control SLE n = 35 (male, mean 40.1 ± 2.3 y, range 17–71 y) Controls n = 33 (male, mean 38.7 ± 2.2 y, range 19–71 y) Exclusion criteria: hypogonadism, therapy with cyclophosphamide, renal failure RIA Serum PRL (mIU/L, mean ± SD) SLE 220.4 ± 15.1 Controls: 190.6 ± 15.5 p = 0.17 SLEDAI (> 2) ≤ 2: 235 ± 23 > 2: 219 ± 20 p = 0.85 Correlation PRL and SLEDAI r s = 0.27 p = 0.12 Serum PRL levels were not higher in subjects with SLE compared to healthy controls and were not correlated with disease activity Cruz et al., 2001 Mexico Case-control SLE n = 35 (5 male, 30 female; mean 34 ± 4 y) Controls n = 10 (2 male, 8 female; mean 34 ± 4 y) Exclusion criteria: pregnancy, lactation, renal/hepatic failure, drugs interfering with serum PRL levels RIA, ELISA, and BA Serum PRL (ng/mL, mean ± SEM) RIA SLE: 12.2 ± 0.9 Controls: 10.2 ± 1.7 p > 0.05 ELISA SLE: 43.6 ± 4.8 Controls: 21.4 ± 7.5 p 0.05 - Serum PRL levels assessed by ELISA but not RIA or BA were higher in subjects with SLE compared to healthy controls Hrycek et al., 2001 Poland Case-control SLE n = 20 (5 male, 15 female; mean 36.5 y, range 31–44 y) Controls n = 17 (4 male, 13 female; mean 36.7 y, range 30–43 y) Exclusion criteria: pregnancy, renal/hepatic failure, drugs interfering with serum PRL levels, rapidly progressive SLE and life-threatening SLE complications RIA Serum PRL (mIU/L) SLE: 355.41 ± 235.37 Controls: 230.53 ± 159.35 p > 0.05 - Serum PRL levels were not higher in subjects with SLE compared to healthy controls Jacobi et al., 2001 Germany Case-control SLE n = 60 (8 male, 52 female; mean 35.6 y) Healthy controls n = 47 (17 male, 30 female; mean 32.9 y) Exclusion criteria: pregnancy, lactation, prolactinoma, hypothyroidism, renal failure, drugs interfering with serum PRL levels ELISA Hyperprolactinemia (> 20 ng/mL): SLE: 17/60 Control: 0/47 Serum PRL (ng/mL; mean ± SD) SLE: All: 17.4 ± 15.1 Male: 12.8 ± 7.5 Postmenopausal female: 12.7 ± 7.0 Premenopausal female: 20.0 ± 17.5 Controls All: 6.3 ± 3.2 Male: 5.5 ± 3.2 Premenopausal female: 6.7 ± 3.2 ECLAM (> 4) Serum PRL according to ECLAM (ng/mL, mean ± SD) ≤ 4: 12.8 ± 9.3 > 4: 22.1 ± 18.2 p = 0.003 Correlation PRL and ECLAM-score r s = 0.54 p < 0.0001 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Pacilio et al., 2001 Italy Case-control SLE n = 78 (5 male, 73 female; median 31 y, range 16–71 y) Controls n = 20 (2 male, 18 female; median 28 y, range 19–60 y) Exclusion criteria: disorders and drugs interfering with serum PRL levels IRMA BA Hyperprolactinemia (> 20 ng/mL): SLE: 21/78 (IRMA), 31/78 (BA) Controls: 0/20 Serum PRL (ng/mL; mean ± SD, range) IRMA SLE: 15.2 ± 9.1, 2.2–51.2 Controls: 8.9 ± 3.2, 3.4–16.2 BA: SLE: 22.2 ± 14.6, 4.2–84 Controls: 12.8 ± 2.7, 3.2–18.4 SLEDAI Serum PRL according to SLEDAI (ng/mL mean, range) ≤ 10: 8.65, 4–14 (IRMA); 12.5, 3.6–20.6 > 10: 19.9, 6.3–51.2; 31.0, 12.4–72.8 (BA) p < 0.001 (IRMA and BA) n = 44 Correlation PRL and SLEDAI IRMA r s = 0.5 p < 0.001 BA r s = 0.41 p < 0.02 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Kramer et al., 2005 Brazil Case-control SLE n = 26 (1 male, 25 female; mean 35.4 ± 11.7 y) Controls n = 28 (2 male, 26 female, mean 49.6 ± 12.9 y) Exclusion criteria: hypothyroidism, pregnancy, lactation, kidney/liver failure, drugs interfering with serum PRL levels CL Serum PRL (ng/mL; mean ± SD) SLE: 21.3 ± 12.6 Controls: 12.5 ± 6.5 p = 0.006 - Serum PRL levels were higher in subjects with SLE compared to healthy controls Hrycek et al., 2007 Poland Case-control SLE n = 25 (4 male, 21 female; mean 43.37 ± 11.85 y, range 18–73 y) Controls n = 24 (4 male, 21 female; mean 52.2 ± 16.18 y, range 18–78 y) Exclusion criteria: pregnancy, lactation, MoMorenal/hepatic failure, drugs interfering with serum PRL levels, rapidly progressive SLE and life-threatening SLE complications IRMA Serum PRL (ng/mL, mean ± SD) SLE: 16.2 ± 10.6 Controls: 8.55 ± 4.97 p < 0.05 - Serum PRL levels were higher in subjects with SLE compared to healthy controls Rastin et al., 2007 Iran Case-control SLE n = 38 (10 male, 28 female; mean 27 y, range 16–47 y) Controls n = 20 (10 male, 10 female; mean 28 y, range 18–42 y) Exclusion criteria: NR RIA Serum PRL (mIU/L, mean ± SD, all) SLE: 24.4 ± 3.1 Controls: 11.2 ± 1.2 p < 0.05 Serum PRL (mIU/L, mean ± SD, female) SLE: 25.08 ± 4.3 Controls: 13.7 ± 2.03 p < 0.05 Serum PRL (mIU/L, mean ± SD, male) SLE: 23.0 ± 4.2 Controls: 8.6 ± 0.74 p < 0.05 - Serum PRL levels were higher in subjects with SLE compared to healthy controls Gómez-Pérez et al., 2003 Venezuela Cross-sectional n = 18 (female; mean 30 ± 10 y, range 18–48 y) Exclusion criteria: pregnancy, renal failure, other causes of hyperprolactinemia RIA - SLEDAI (> 4) Serum PRL according to SLEDAI (ng/mL mean ± SD) ≤ 4: 10.84 ± 3.64 > 4: 37.95 ± 33.78 Serum PRL levels were correlated with disease activity Vera-Lastra et al., 2003 US Case-control SLE n = 43 (female) No renal involvement: mean 27.7 ± 11.1 y Renal involvement: mean 28.6 ± 5.2 y Controls n = 36 (female; mean 28.3 ± 10.3 y) Exclusion criteria: pregnancy, renal/hepatic failure, hypothyroidism, seizures, drugs interfering with serum PRL levels IRMA Serum PRL (ng/mL, mean ± SD) SLE: 23.55 ± 5.88 Controls: 6.43 ± 2.24 p < 0.0001 SLEDAI Correlation PRL and SLEDAI (linear regression) r = 0.4946 p = 0.0007 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Dai et al., 2006 US Case-control SLE n = 80 (9 male, 71 female; mean 31.8y, range 12–58 y) Controls n = 25 (6 male, 19 female, mean 34.8 ± 13.0 y) Exclusion criteria: pregnancy, prolactinoma, hypothyroidism, renal failure, liver disease, drugs interfering with serum PRL levels IRMA Hyperprolactinemia (> 480 µIU/mL in male and 650 µIU/mL in female): SLE: 32/80 Controls: 0/25 p < 0.001 Serum PRL (µIU/mL; mean ± SD) SLE (active): 718 ± 274 µIU/mL SLE (inactive): 476 ± 156 µIU/mL Controls: 274 ± 135 µIU/mL p 9) Serum PRL according to SLEDAI (µIU/mL; mean ± SD) ≤ 9: 718 ± 274 µIU/mL > 9: 476 ± 156 µIU/mL Correlation PRL and SLEDAI r p = 0.638 p < 0.001 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Haghighi et al., 2006 Iran Case-control SLE n = 35 (4 male, 31 female; mean 26.7 y, range 9–54 y) Controls n = 60 (8 male, 52 female, mean 28.3 y, range 13–48 y) Exclusion criteria: pregnancy, lactation, renal/hepatic failure, hypothyroidism, seizures, drugs interfering with serum PRL levels IRMA Hyperprolactinemia (> 721 mIU/L for female and < 414 mIU/L for male) SLE: 10/35 Controls: 2/60 p < 0.05 Serum PRL (mIU/L, mean ± SD) SLE: 770 ± 860 Controls: 341 ± 335 p = 0.0078 SLEDAI Correlation PRL and SLEDAI r = NR p = 0.004 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Leaños-Miranda et al., 2006 Mexico Cross-sectional n = 259 (16 male, 243 female; mean 35.5 ± 11.2 y) Exclusion criteria: NR (none of the included subjects had obvious causes of hyperprolactinemia) IRMA Hyperprolactinemia Free PRL: 56/259 Serum PRL (ng/mL; median and range) Total PRL: 13.8, 1.2-281.7 Free PRL: 9.8, 1.3-105.6 SLEDAI (> 4) Serum PRL according to SLEDAI (ng/mL; median) Total PRL ≤ 4: 20.1 ng/mL > 4: 22.7 ng/mL p = 0.53 Free PRL ≤ 4: 9.3 ng/mL > 4: 12.6 ng/mL p < 0.001 Correlation PRL and SLEDAI Total PRL r p = 0.09 p = 0.15 Free PRL r p = 0.31 p < 0.001 Serum free but not total PRL levels were correlated with disease activity Rezaieyazdi et al., 2006 Iran Cross-sectional n = 30 (4 male, 26 female, mean 24.5 y, range 5–50 y) Exclusion criteria: pregnancy, lactation, pituitary adenoma, renal/liver failure, thyroid disorder, drugs that interfere with serum PRL levels IRMA Hyperprolactinemia (> 16 ng/mL in male and 25 ng/mL in female): 10/30 Serum PRL (ng/mL; mean ± SD, range) All: 33.8 ± 19.8, 7–85 Male: 4.9 ± 4.9, 13–23 Female: 35.6 ± 20.3, 7–85 SLAM Correlation PRL and SLAM r p = 0.675 p < 0.001 Serum PRL levels were correlated with disease activity Cárdenas-Mondragón et al., 2007 France Cross-sectional n = 98 (5 male, 93 female; mean 33.0 ± 10.5 y) Exclusion criteria: NR (none of the included subjects had obvious causes of hyperprolactinemia) IRMA - SLEDAI (> 4) Serum PRL according to SLEDAI (ng/mL; mean ± SD or median, range) Total PRL ≤ 4: 19.9 ± 28.8 > 4: 22.9 ± 17.4 p = 0.49 Free PRL ≤ 4: 10.6 ± 6.0 > 4: 17.9 ± 18.1 p = 0.008 Correlation PRL and SLEDAI Total PRL r s = 0.074 p = 0.47 Free PRL r s = 0.44 p < 0.001 Serum free but not total PRL levels were correlated with disease activity Elwakkad et al., 2007 Egypt Case-control SLE n = 12 (2 male, 10 female; mean 15.8 ± 2.9 y) Controls n = 21 (age and sex-matched) Exclusion criteria: NR EIA Serum PRL (ng/mL; mean ± SD, range) SLE: 424.167 ± 119.58 Controls: 284.17 ± 96.24 p < 0.05 SLEDAI Correlation PRL and SLEDAI Total PRL r s = 0.975 p < 0.0001 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Jokar et al., 2008 Iran Cross-sectional n = 90 (7 male, 83 female; mean 27.6 ± 9.1 y, range 14–52 y) Exclusion criteria: pregnancy, lactation, menopause, primary amenorrhea, previous history of hysterectomy, oophorectomy, and current use of oral contraceptive agents RIA Hyperprolactinemia (> 28 ng/mL): 9/90 Serum PRL (ng/mL, mean ± SD, range): 17.55 ± 8.4, 6–48 SLEDAI (> 4) Hyperprolactinemia according to SLEDAI ≤ 4: 2/33 > 4: 7/57 p = 0.343 Serum PRL according to SLEDAI (ng/mL; mean) ≤ 4: 17.94 > 4: 8.68 p = 0.563 Serum PRL levels were not correlated with disease activity Shabanova et al., 2008 Russia Case-control SLE n = 94 (female; mean 29.2 ± 7 y, range 16–45 y) Controls n = 40 Exclusion criteria: pregnancy, lactation, menopause, primary amenorrhea, previous history of hysterectomy, oophorectomy, and current use of oral contraceptive agents ELISA Hyperprolactinemia (> 726 mIU/mL): SLE: 9/94 Controls: 0/40 Serum PRL (mIU/mL, mean and range): SLE: 274, 272–563 Controls: 344, 227–438 p 10) Serum PRL according to SLEDAI (mIU/mL; mean and range) ≤ 10: 347, 263–486 > 10: 450, 275–675 p < 0.05 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Paraiba et al., 2010 Brazil Case-control SLE n = 30 (3 male, 27 female; median 32 y, range 20–48 y) Controls n = 10 (1 male, 9 female; median 31.5 y, range 24–42 y) Exclusion criteria: pregnancy, prolactinoma, hypothyroidism, renal failure, drugs interfering with PRL serum levels IFMA Hyperprolactinemia (> 14.5 ng/mL): SLE: 8/30 Controls: 0/10 Serum PRL (ng/mL, median and range): SLE: 9.65, 1.9–38.9 Controls: 6.4, 2.4–10.3 SLEDAI (> 4) Hyperprolactinemia according to SLEDAI ≤ 4: 1/12 > 4: 7/18 p = 0.02 Serum PRL according to SLEDAI (ng/mL; median and range) ≤ 4: 7.65, 1.9–15.5 > 4: 10.85, 5-38.9 p = 0.01 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Shahin, 2011 Saudi Arabia Cross-sectional n = 33 (female; mean 29.3 ± 9.5 y, range 13–45 y) Exclusion criteria: renal and/or hepatic failure, pregnancy, hypothyroidism, drugs interfering with serum PRL levels IRMA Hyperprolactinemia (> 511 mIU/mL): 10/33 Serum PRL (mIU/mL, mean ± SD and range): 680.7 ± 1021.5, 198–4500 SLEDAI (> 4) Serum PRL (mIU/mL, mean ± SD) ≤ 4: 331.5 ± 129.9 > 4: 728.9 ± 1082 p > 0.05 Correlation PRL and SLEDAI r p = 0.09 p > 0.05 Serum PRL levels were not correlated with disease activity Orbach et al., 2012 Hungary and Italy Cross-sectional n = 256 (31 male, 225 female; median 36.5 y) Exclusion criteria: NR CL Hyperprolactinemia (> 498 mIU/L in male and 392 mIU/L in female) 45/256 ECLAM (> 2, Italy) and SLEDAI (> 4, Hungary) ECLAM or SLEDAI not associated with the presence of hyperprolactinemia (data NR) Serum PRL levels were not correlated with disease activity Karimifar et al., 2013 Iran Cross-sectional n = 60 (female; median 31 y, range 15–60 y) Exclusion criteria: pregnancy, prolactinoma, hypothyroidism, serum creatinine > 2 mg/dL RIA Hyperprolactinemia (> 20 ng/mL): 5/60 SLEDAI Correlation PRL and SLEDAI Total PRL r s = 0.062 p = 0.39 Serum PRL levels were not correlated with disease activity Zhu et al., 2015 China Case-control SLE n = 47 (5 male, 42 female; mean 34.1 ± 2.5 y, range 15–53 y) Controls n = 10 (1 male, 9 female; mean 30 y, range 18–50 y) Exclusion criteria: subjects with active SLE treated with corticosteroids or immunosuppressants, subjects with inactive SLE treated with prednisone at doses over 5–15 mg/d, abnormal thyroid function, other autoimmune diseases FIA Serum PRL (unit NR; mean ± SD) SLE (active): 14.45 ± 7.25 SLE (inactive): 11.79 ± 8.02 Controls: 7.08 ± 6.26 p 4) Hyperprolactinemia according to SLEDAI ≤ 4: 3/13 > 4: 18/34 p 4: 14.45 ± 7.25 p > 0.05 Serum PRL levels were higher in subjects with SLE compared to healthy controls, hyperprolactinemia frequency was higher in subjects with active SLE, serum PRL levels were not different between subjects with active and inactive SLE Aulestia et al., 2016 Colombia Cross-sectional n = 50 (female; mean 37 ± 14 y, range 16–65 y) Exclusion criteria: hormone replacement therapy, prolactinoma, hysterectomy/oophorectomy, pregnancy, lactation, other rheumatic diseases, chronic renal disease, hypothyroidism, drugs interfering with serum PRL CL Serum PRL (ng/mL, median): 7.07 SLEDAI (> 6) Serum PRL according to SLEDAI (ng/m; mean and IQR) ≤ 6: 7.06, 5.1–10.2 > 6: 9.7, 5-11.25 p = 0.7 Serum PRL levels were not correlated with disease activity Gómez-Hernández et al., 2016 Venezuela Cross-sectional n = 50 (female; mean 31 ± 10.9 y in patients with active disease and 36 ± 10.4 in patients with inactive disease) Exclusion criteria: pregnancy, lactation, prolactinoma, drugs interfering with serum PRL CL Hyperprolactinemia (> 25 ng/mL): 4/50 SLEDAI (> 3) Hyperprolactinemia (> 25 ng/mL) according to SLEDAI ≤ 3: 0/22 > 3: 4/28 p = 0.044 Serum PRL according to SLEDAI (ng/mL; mean and IQR) ≤ 3: 14.2 ± 7.2 > 3: 39.0 ± 59.5 p = 0.044 Serum PRL levels were correlated with disease activity Toffoli-Ribeiro et al., 2016 Brazil Case-control SLE n = 62 (female; mean 35.4 ± 12.2 y) Controls n = 29 (female; mean 32.0 ± 5.1 y) Exclusion criteria: pregnancy, lactation, prolactinoma, drugs interfering with serum PRL, chronic renal failure CL Hyperprolactinemia (> 25 ng/mL) SLE: 14/73 Controls: 0/29 Serum PRL (ng/mL, mean): SLE: 12.0 Controls: 8.8 p = 0.02 SLEDAI Serum PRL according to SLEDAI (ng/mL; median and IQR) 0: 8.4, 4.9–13.9 1–5: 7.9, 6.1–14.2 6–10: 7.7, 5.5–17.4 > 10: 17.1, 10.6–28.4 Hyperprolactinemia (> 25 ng/mL) according to SLEDAI 0: 5/46 1–5: 4/31 6–10: 3/27 > 10: 10/31 p < 0.05 Correlation PRL and SLEDAI Total PRL r s = 0.47 p = 0.0001 Free PRL r s = 0.51 p < 0.0001 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Yang et al., 2016 China Case-control SLE n = 30 (1 male, 29 female; mean 37.7 ± 14.1 y) Controls n = 50 (1 male, 24 female; mean 38.4 ± 9.2 y) Exclusion criteria: NR ECLIA Serum PRL (mIU/L, mean ± SD) SLE: 580 ± 419.9 Controls: 346.0 ± 227.6 p 5) Serum PRL according to SLEDAI (mIU/L; mean ± SD) ≤ 5: 706.1 ± 485.5 > 5: 393.2 ± 191.3 p < 0.05 Correlation PRL and SLEDAI r s = 0.481 p < 0.01 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Iqbal et al., 2017 Pakistan Case-control SLE n = 35 (female; mean 23.48 ± 0.63 y) Controls n = 35 (female; mean 31.25 ± 0.88 y) Exclusion criteria: steroid therapy, hormone replacement therapy or contraceptive pills, diabetes, liver diseases, hormonal disorders ELISA Serum PRL (ng/mL, mean ± SD) SLE: 65.45 ± 4.08 Controls: 9.06 ± 0.59 p < 0.001 DUSOI Correlation PRL and DUSOI r s = 0.729 p < 0.01 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity Abdelaziz et al., 2018 Egypt Cross-sectional n = 60 (female; mean 33.5 ± 13.12 y, range 17–58 y) Exclusion criteria: renal and/or hepatic failure, pregnancy, lactation, hypothyroidism, drugs interfering with serum PRL levels, sex hormones (oral contraceptives, hormone replacement therapy) Immunoassay (VIDAS) Hyperprolactinemia (> 25 ng/mL: 15/60 Serum PRL (ng/mL, mean ± SD): 19.55 ± 12.59 SLEDAI (> 5) Hyperprolactinemia according to SLEDAI (%) ≤ 5: 3/14 > 5: 12/46 Correlation PRL and SLEDAI r p = 0.177 p = 0.323 Serum PRL levels were not correlated with disease activity Wan-Asyraf et al., 2018 Malaysia Cross-sectional n = 43 (1 male, 42 female; median: 33 y, IQR 30–36 y) Exclusion criteria: pituitary adenoma, hypothyroidism, drugs interfering with serum PRL levels, sex hormones, chronic renal disease, increased serum levels of liver enzymes and bilirubin, pregnancy, lactation, infection, menopause Chemiflex Hyperprolactinemia (> 16 ng/mL for male and 20 ng/mL for female): 12/43 SLEDAI (> 4) Hyperprolactinemia according to SLEDAI ≤ 4: 6/31 > 4: 6/12 p = 0.044 Serum PRL according to SLEDAI (ng/mL, median and IQR) ≤ 4: 14.34, 11.09–18.70 > 4: 19.91, 15.95–22.65 p = 0.014 Correlation PRL and SLEDAI r s = 0.449 p = 0.003 Serum PRL levels were correlated with disease activity Raeisi et al., 2018 Iran Case-control SLE n = 40 (female; mean 27.3 ± 4.12 y) Controls n = 41 (female; mean 28.4 ± 6.65 y) Exclusion criteria: PCOS, pregnancy, lactation, menopause, abnormal serum levels of liver enzymes, abnormal thyroid function, other autoimmune diseases, drugs interfering with serum PRL levels IEA Serum PRL (ng/mL, mean ± SD) SLE: 67.82 ± 7.4 Controls: 41.26 ± 5.8 P < 0.001 SLEDAI Serum PRL (ng/mL, mean ± SD) Mild activity (SLEDAI 4–10): 62.55 ± 4.4 Moderate activity (SLEDAI 11–19): 74.25 ± 4.6 p < 0.001 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were higher in subjects with SLE and moderate disease activity compared to those with mild disease activity Soliman et al., 2018 Egypt Case-control SLE n = 45 (3 male, 42 female; mean 31 ± 7.7 y, range 18–53 y) Controls n = 45 (20 male, 25 female; mean 29.3 ± 10.5 y, range 16–58 y) Exclusion criteria: pregnancy, lactation, prolactinoma, drugs interfering with serum PRL, chronic renal failure, hepatic failure, endocrinopathies, psychiatric disorders ECLIA Serum prolactin (ng/mL, mean ± SD and range) SLE: 13 ± 5.3, 6–27 Controls: 11.8 ± 4.2, 5–20 p > 0.05 SLEDAI Serum PRL according to SLEDAI (ng/mL, mean ± SD and range) 1–5: 15.7 ± 3, 6–23 6–10: 16 ± 4, 8–27 11–19: 21.8 ± 5, 10–28 20: - p = 0.007 Correlation PRL and SLEDAI (type of correlation coefficient NR) r = 0.022 p = 0.907 Serum PRL levels were not higher in subjects with SLE compared to healthy controls, were not overall correlated with disease activity, but increased with increasing SLEDAI score Soliman et al., 2023 Egypt Case-control SLE n = 40 (6 male, 34 female; mean 11.5 ± 2.1 y) Controls n = 40 (7 male, 33 female; mean 10.7 ± 1.9 y) Exclusion criteria: hypothyroidism, prolactinoma, renal failure, drugs interfering with serum PRL ELISA Serum prolactin (ng/mL, mean ± SD) SLE: 17.3 ± 6.6 Controls 13.5 ± 5.3 p = 0.005 SLEDAI Serum PRL according to SLEDAI (ng/mL, mean ± SD and range) 4–8: 14.0 ± 6.2 8–12: 17.0 ± 5.3 > 12 : 19.3 ± 7.7 p = 0.212 Correlation PRL and SLEDAI r p = 0.368 p = 0.019 Serum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity NR: not reported BA: biological assay; Chemiflex: chemiluminescent microparticle immunoassay technology with flexible assay protocols; CL: chemoluminescence; DUSOI: Duke Severity of Illness Checklist; ECLAM: European Consensus Lupus Activity Measurement Index; ECLIA: electrochemiluminescence immunoassay; EIA: immunoenzymatic assay; ETA: Enzymun-test assay; FIA: fluorescence immunoassay; IEA: immunoenzymometric assay; IFMA: immunofluorometric assay; IQR: interquartile range; IRMA: immunoradiometric assay; MEIA: Microparticle Enzyme Immunoassay; PRL: prolactin; RIA: radioimmunoassay; r p : Pearson’s correlation coefficient; r s : Spearman’s correlation coefficient; SEM: standard error of mean; SLAM: Systemic Lupus Activity Measure; SLE: Systemic Lupus Erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. Characteristics of studies examining the effect of dopaminergic agonists on circulating prolactin concentration in systemic lupus erythematosus The characteristics of the included studies are summarized in Table 2 . The studies were conducted in the United States 68 , Mexico 69 , Poland 55 , 56 , 69 , and China 70 . Three studies were prospective open-label trials 55 , 56 , 68 , and two were randomized clinical trials 69 , 70 . Two studies with the prospective open-label design included healthy controls to compare the serum levels of inflammatory markers 55 , 56 . Sample sizes ranged from 7 to 38 subjects with SLE. Three studies assessed the effect of bromocriptine on SLE activity 68 – 70 , whereas two studies investigated the impact of quinagolide 55 , 56 . Notably, none of the studies included subjects with rapidly progressive or life-threatening SLE. Table 2 Characteristics of included studies (n = 5). Author, year, country Study design, aim Sample size, gender Treatment regimen, follow-up time Method for serum PRL assessment, PRC serum levels Method for disease activity assessment Results Conclusion McMurray et al., 1995 United States Prospective open-label trial To investigate the efficacy of BRC in suppressing SLE activity n = 7 (5 female, 3 male); 26–48 y BRC: 1.25 mg/d, 1 wk; 2.5 mg/d and monthly 1.25 to 2.5 mg/d increments until serum PRL < 3 ng/mL (3.75–7.5 mg/d) 6–9 mo during treatment; 5 mo after treatment withdrawal NR Before: 11.2 ± 1.9 ng/mL 6 mo: 3.1 ± 1.7 ng/mL After BRC withdrawal: 22.1 ± 4 ng/mL SLEDAI and SLAM SLEDAI score before and after treatment Before: 16.0 ± 2.0 At 6 mo: 5.9 ± 0.8 P = 0.02 SLAM score before and after treatment Before: 11.3 ± 0.9 At 6 mo: 6.0 ± 1.6 P = 0.03 2 mo after BRC withdrawal: 10.4 ± 1.8 P = 0.02 (vs at 6 mo) 4 mo after BRC withdrawal: 11.4 ± 0.8 P = 0.03 (vs at 6 mo) BRC treatment reduced SLEDAI score at the 6th month of follow-up Alvarez et al., 1998 Mexico Randomized clinical trial To investigate the efficacy and safety of BRC as an adjunct to conventional SLE treatment BRC: n = 36 (35 female, 1 male); 31.5 ± 9.4 y Control: n = 30 (28 female, 1 male); 32.2 ± 13.2 y BRC, 2.5 mg/d BRC: 2–17 mo (13.1 ± 3.8 mo) Control: 1–17 mo (11.9 ± 5.6) ELISA Baseline BRC: 24.8 ± 18.4 ng/mL Control: 23.7 ± 22.1 ng/mL p = 0.42 12 mo BRC: 5.8 ± 9 ng/mL Control: 20.3 ±14.0 ng/mL P = 0.001 SLEDAI SLEDAI score during follow-up Mo 1–4; 6–12 BRC vs control: ns Mo 5: BRC: 0.9 ± 1.4 Control: 2.0 ± 4.5 p < 0.05 No of flares BRC: 16 (50%) Control: 11 (42%) p = 0.74 Mean flares/patient/mo BRC: 0.08 ± 0.11 Control: 0.18 ± 0.27 p = 0.03 BRC treatment reduced SLEDAI score at the 5th month of follow-up and mean number of flares/patient/month Hrycek et al. 2001 Poland Prospective open-label trial To determine the effect of QNL on serum levels of cytokines in subjects with SLE SLE: 20 (15 female, 5 male); 31–44 y Control: 17 (13 female, 4 male); 30–43 y (for comparison of cytokine serum levels) QNL: 12.5 mcg/d, 1 mo; 25 mcg/d, 1 mo; 50 mcg/d, 4 mo 6 mo RIA Baseline SLE: 355.41 ±235.37 mIU/L Control: 230.53 ± 159.25 mIU/L p > 0.05 3 mo SLE: 281.95 ± 181.07 mIU/L P > 0.05 (vs baseline) 6 mo: 195.51 ± 109.14 mIU/L P < 0.05 (vs baseline) SLEDAI SLEDAI score before and after treatment Before: 13.2 ± 2.6 After: 5.0 ± 3.0 p < 0.05 QNL treatment for 6 mo reduced SLEDAI score Hrycek et al. 2007 Poland Prospective open-label trial To determine the effect of QNL on SLEDAI score, acute phase proteins, and IL-6 in subjects with SLE SLE: 25 (21 female, 4 male); 43.37 ± 11.85 y Control: 25 (21 female, 4 male); 52.20 ± 16.18 y QNL: 12.5 mcg/d, 1 mo; 25–50 mcg/d, 3 mo 3 mo IRMA Baseline SLE: 16.2 ± 10.6 ng/mL Control: 8.55 ± 4.97 ng/mL P < 0.05 3 mo SLE: 9.33 ± 4.93 ng/mL P < 0.05 (vs baseline) SLEDAI SLEDAI score before and after treatment Before: 13.4 ± 2.4 After: 7.56 ± 3.61 p < 0.05 QNL treatment for 3 mo reduced SLEDAI score Qian et al., 2015 China Randomized clinical trial To investigate the efficacy and safety of BRC as an adjunct to conventional SLE treatment in the postpartum period BRC: 38 (female); 30.47 ± 4.33 y Control: 38 (female); 30.02 ± 3.95 y BRC, 2.5 mg bid, 14 d (12h after delivery) 12 mo RIA 2 wk after delivery BRC: 8.6 ± 5.0 ng/mL Control: 72.6 ± 32.6 ng/mL P < 0.001 2 mo after delivery BRC: 11.5 ± 7.1 ng/mL Control: 25.7 ± 37.6 ng/mL P < 0.05 SLEDAI SLEDAI score Baseline BRC: 7.13 ± 1.37 Control: 6.92 ± 1.98 p = 0.43 6 mo BRC: 4.25 ± 1.28 Control: 5.85 ± 1.76 p < 0.001 12 mo BRC: 3.42 ± 0.95 Control: 4.53 ± 1.15 p < 0.05 BRC treatment for two wk following delivery reduced SLEDAI score at 6 and 12 mo BRC: bromocriptine, ELISA: enzyme-linked immunosorbent assay, IRMA: immunoradiometric assay, NR: not reported, QNL: quinagolide, RIA: radioimmunoassay, SLAM: SLE Activity Measure; SLE: systemic lupus erythematosus, SLEDAI: Systemic Lupus Erythematosus Disease Activity Index. Hyperprolactinemia in systemic lupus erythematosus versus healthy controls Thirteen case-control studies 29 , 38 , 44 , 47 , 49 – 51 , 54 , 57 , 58 , 60 , 62 , 64 compared the frequency of hyperprolactinemia between subjects with SLE and healthy controls, involving 952 participants. The mean frequency of hyperprolactinemia among subjects with SLE was 30.1%, ranging from 7.1–87.5%. Pooling data from individual studies revealed that subjects with SLE had a significantly increased odds of hyperprolactinemia (OR 11.69, 95%CI 5.64–24.22, p < 0.00001, I 2 = 0%, Fig. 3 A) The frequency of hyperprolactinemia was described in nine cross-sectional studies 13 , 15 , 31 , 32 , 37 , 39 , 45 , 59 , 63 , with a mean of 17%, ranging from 2.19 to 33.3%. Funnel plot analysis indicated evidence of small studies effect on the association between hyperprolactinemia and SLE (Appendix I). Circulating prolactin levels in systemic lupus erythematosus versus healthy controls Twenty-eight studies compared circulating PRL levels between subjects with SLE and healthy controls, comprising 1,860 individuals 27 – 30 , 33 – 36 , 38 , 40 , 41 , 43 , 44 , 47 – 52 , 54 – 58 , 60 , 62 , 65 , 67 . Data from 23 studies, including 1,411 subjects 27 – 30 , 33 – 36 , 40 , 43 , 44 , 48 – 50 , 52 , 54 – 58 , 60 , 62 , 67 were pooled and revealed that PRL levels were significantly higher among subjects with SLE than in healthy controls (SMD 1.96, 95%CI 1.27–2.65, p < 0.00001, I 2 = 95%, Fig. 3 B). Data from three studies could not be included in the meta-analysis due to lack of description of error values for serum PRL levels 38 , 47 , 51 . One study was excluded from the meta-analysis because overall PRL levels in subjects with SLE were not presented but only according to disease activity status 41 , and one study was excluded from the meta-analysis because PRL was assessed by an assay with serum levels not comparable to the other studies 65 . Notably, the five excluded studies reported significantly higher circulating PRL levels in individuals with SLE than healthy controls. Funnel plot analysis indicated evidence of small studies effect on the difference between circulating PRL levels between subjects with SLE and healthy controls (Appendix I). Hyperprolactinemia and systemic lupus erythematosus activity Seven studies examined the association between hyperprolactinemia and SLE activity assessed by the SLEDAI 15 , 31 , 41 , 45 , 50 , 51 , 63 , and data from six 15 , 31 , 41 , 45 , 50 , 63 were pooled in the meta-analysis. Hyperprolactinemia was associated with increased SLEDAI scores (OR 3.02, 95% CI 1.52-6.00, p 0.002, I 2 = 0%, Fig. 4 A). Four studies found that hyperprolactinemia was significantly associated with a SLEDAI score greater than 4 15,31,41,50 , which was used as the cutoff value to define disease activity. Only one study used SLEDAI greater than 3 45 or greater than 5 63 . The first found that hyperprolactinemia was marginally associated with disease activity, whereas the latter found no association. One study was not excluded in the meta-analysis because the frequency of hyperprolactinemia was described for various ranges of SLEDAI scores 51 but described that hyperprolactinemia was significantly associated with disease activity. Funnel plot analysis indicated evidence of small studies effect on the association between hyperprolactinemia and SLE activity (Appendix J). Correlation between circulating prolactin levels and systemic lupus erythematosus activity A total of 26 studies comprising 1,563 subjects addressed the correlation between circulating PRL levels and disease activity 12 , 15 , 26 , 29 , 30 , 32 – 34 , 37 , 39 , 40 , 44 , 47 , 51 – 53 , 57 – 61 , 63 – 67 . Nineteen studies employing the SLEDAI to assess disease activity and involving 1,153 individuals could be pooled in the meta-analysis 12 , 15 , 26 , 32 – 34 , 39 , 40 , 44 , 47 , 51 – 53 , 58 , 60 , 63 , 65 – 67 . Circulating PRL was positively associated with the SLEDAI score (correlation coefficient: 0.38; 95%CI 0.26–0.48, p < 0.001, I 2 = 79.5%, Fig. 4 B). When data from studies including other score systems to assess SLE activity were pooled, we found that circulating PRL was positively associated with disease activity (correlation coefficient: 0.34; 95%CI 0.21–0.45, p < 0.001, I 2 = 81.5%, 24 studies, 1,313 individuals, Appendix K). Among studies included in the latter meta-analysis, two used the ECLAM score to assess disease activity 57 , 61 , one used the SLAM score 37 , and one study used the DUSOI score 30 . Two studies were excluded from the meta-analysis because they did not report the correlation coefficient value 29 , 59 . Funnel plot analysis indicated evidence of small studies effect on the correlation between circulating PRL levels and SLE activity (Appendix J). The effect of dopaminergic agonists on systemic lupus erythematosus activity One prospective open-label trial 68 and two randomized clinical trials 69 , 70 assessed the effect of adjunct bromocriptine treatment on measures of SLE activity. All three studies reported that adding bromocriptine to SLE therapy reduced disease activity. McMurray et al. (1995) assessed seven subjects and reported that bromocriptine at maintenance doses ranging from 3.75 to 7.5 mg for six months significantly reduced SLEDAI and SLAM scores 68 . Alvarez-Nemegyei et al. (1998) conducted a randomized clinical trial in which participants were assigned to receive bromocriptine (2.5 mg/d) or placebo and assessed monthly for up to 12 months. SLEDAI score was significantly lower in the treated group compared to placebo at the fifth month, but not at other time points. Additionally, bromocriptine treatment significantly decreased the mean flare/patient/month 69 . More recently, Qian et al. (2015) reported that bromocriptine treatment at 5 mg/d for 14 days, beginning 12 hours after delivery, significantly reduced SLEDAI score at 6 and 12 months compared to placebo 70 . Two prospective open-label trials investigated whether adjuvant quinagolide treatment affected SLE activity. Hrycek et al. (2001) reported that quinagolide treatment (50 mcg/d, maintenance dose) for six months significantly decreased SLEDAI score compared to baseline in 20 subjects 55 . Similarly, Hrycek et al. (2007) found that quinagolide at 50 mcg/d (maintenance dose) for three months significantly reduced SLEDAI score compared to baseline in 25 subjects 56 . Due to their heterogeneous design, we could not pool the data from the included studies in a meta-analysis. Risk of bias across studies All 15 cross-sectional studies addressing the association between circulating prolactin levels and SLE were considered to have a low risk of bias (Appendix D), whereas two case-control studies were considered to have a high risk of bias and 27 to have a low risk of bias (Appendix E). All three open-label trials investigating the effect of dopaminergic agonists on SLE activity were considered to have a low risk of bias (Appendix F), whereas one randomized clinical trial was considered to have a low risk of bias, and the other randomized clinical trial was considered to have a moderate risk of bias (Appendix G). Discussion In this systematic review and meta-analysis, we examined whether circulating PRL concentration was different in subjects with SLE compared with healthy controls and whether it was associated with disease activity in SLE. We found that hyperprolactinemia rate and serum PRL levels were significantly higher among individuals with SLE than controls and that serum PRL was moderately correlated with disease activity. In addition, we found that adjunct treatment of SLE with bromocriptine or quinagolide significantly decreased disease activity assessed by the SLEDAI score. The association between circulating PRL levels and SLE was addressed in a previous meta-analysis of 25 studies comprising 1,056 subjects with SLE and 426 healthy controls, which reported that circulating PRL levels were significantly higher in SLE than controls and were significantly associated with disease activity 17 . Our study contributed with updated data from studies published over the last seven years and by additionally examining the effect of PRL suppression on SLE activity. We conducted a detailed literature search and captured 13 additional studies published until 2016 and six studies published since then. In addition to examining circulating PRL levels in SLE and its association with disease activity, we examined the rate of hyperprolactinemia in subjects in SLE. Hence, our study contributed with updated data from studies published over the last seven years and reinforced the previous findings. Moreover, we additionally examined the effect of dopamine agonists on SLE activity. To our knowledge, this is the first systematic review addressing this question. The association between circulating PRL and SLE activity in concert with the findings that PRL suppression with dopaminergic agonists decreases disease activity could imply that the association between serum PRL levels and SLE activity is causal. This is further reinforced by the evidence from preclinical studies supporting that the role of PRL in modulating SLE activity is biologically plausible. PRL affects different aspects of innate and acquired immunity. PRL stimulates the inflammatory and phagocytic activity of macrophages 7 – 9 and enhances antigen presentation by activating dendritic cells and inducing the expression of both class II histocompatibility molecules and costimulatory molecules such as CD40, CD80, and CD86 9,71 . Regarding acquired immunity, PRL induces CD4 and CD8 lymphocyte activation by promoting interleukin 2 secretion and inducing the expression of receptors for the latter cytokine, decreasing autoreactive B lymphocyte apoptosis, reducing the threshold for B lymphocyte activation, and increasing immunoglobulin production 9 , 71 , 72 . Studies involving experimental models of SLE also suggest that hyperprolactinemia may lead to immune dysfunction. In NZB/WF1 mice, which spontaneously develop SLE, hyperprolactinemia induced by pituitary transplants enhances immune dysfunction, organ damage, and increased mortality in both females 73 and males 74 . PRL administration to R4A-γ2B Balb/c mice induced a lupus-like phenotype, which was reversible following PRL discontinuation 75 . However, the same effect of PRL was not observed in R4A-γ2B C57BL/6 mice, suggesting that the effects of PRL on immune function depend upon the genetic background 76 . These findings reinforce the complex pathogenesis of SLE, and it is still unclear how PRL interacts with other factors to affect SLE development and phenotype. The role of PRL in modulating immune function has attracted attention to its possible role in affecting autoimmune disease development and severity in humans 9 . SLE is considered the prototype systemic autoimmune disease, and there is increasing evidence that PRL may impact immune dysfunction and the clinical phenotype in SLE 9 . Our meta-analysis reinforces that circulating PRL levels are higher in subjects with SLE than healthy controls and that higher PRL levels are associated with disease activity scores. In light of these findings, we sought to investigate whether decreasing serum PRL would affect SLE activity by conducting a systematic review. Despite the scarcity of studies addressing this question, all five studies included in the review demonstrated that suppressing PRL secretion benefits subjects with SLE. The beneficial impact of PRL suppression with dopaminergic agonists supports the role of PRL in determining SLE activity. However, the latter also points to the potential benefit of dopaminergic signaling itself. Indeed, it was previously shown that bromocriptine can affect the immune system independently from hyperprolactinemia. In cell-based studies, dopaminergic signaling induced by agonists reduced the phagocytic activity of macrophages, decreased B lymphocyte proliferation and differentiation in response to mitogenic stimuli, and inhibited the production of interleukin 1 by T lymphocytes 73 , 77 . In addition, Blank et al. (1990) showed that the addition of bromocriptine to cyclosporine in the treatment of subjects with SLE and uveitis reduced the levels of nuclear autoantibodies compared to cyclosporin, independently from circulating prolactin concentrations 78 . However, to our knowledge, no other human studies have addressed whether dopaminergic agonists could affect SLE activity independently from their action to suppress PRL secretion. It is also unknown whether dopaminergic agonists would be beneficial as monotherapy in subjects with mild disease or how they would affect disease activity compared to established therapy. All included studies in this systematic review assessed the effect of bromocriptine or quinagolide as adjunctive therapy in subjects with SLE. Interestingly, Walker et al. (1999) presented the preliminary findings from a blind randomized clinical trial involving 24 subjects with active SLE, but not organ-threatening disease assigned to receive bromocriptine to lower serum prolactin levels to less than 1 ng/mL (n = 11) or hydroxychloroquine at 6 mg/kg (n = 13). After one year of treatment, the mean SLEDAI score decreased from 8.6 ± 2.6 to 2.5 ± 1.5 in subjects receiving bromocriptine and from 8.2 ± 1.7 to 4.6 ± 1.1 in subjects receiving hydroxychloroquine. Additionally, the proportion of individuals decreasing or stopping prednisone, or starting or increasing prednisone dose was similar in both groups 24 . Although this study was not published as a full-text article, its findings suggest that bromocriptine is comparable to hydroxychloroquine in mild and non-organ-threatening SLE. Another possibility that should be considered is that circulating PRL may be a biomarker of SLE activity instead of having a significant contributory role in disease activity. Indeed, hyperprolactinemia has been reported in different autoimmune diseases, as thoroughly reviewed elsewhere 16 , 79 , and also in non-autoimmune inflammatory disorders, such as insulin resistance 80 , 81 and atherosclerosis 82 , 83 . However, prospective studies are warranted to validate circulating PRL as a disease biomarker. It is noteworthy that eight studies reported that circulating PRL levels were not different between subjects with SLE and healthy controls 33 , 34 , 55 , 59 , 61 , 62 , 64 , 67 , and 13 studies found no correlation between circulating PRL and SLE activity 13 , 26 , 31 – 34 , 39 , 42 , 54 , 58 , 63 , 64 , 67 . The reasons for the inconsistent findings between studies are not clear. However, they could be due to the different characteristics of the participants and to characteristics of the association between PRL and SLE and its activity that were not addressed in the methodological design of the included studies. It is reasonable to speculate that sustained but not sporadic increases in circulating PRL could determine its association with immune dysfunction, and a single measurement of serum PRL levels, as was the case in all included studies, would lead to inappropriate conclusions. Another point that should be considered in interpreting our findings is that posttranslational changes in PRL may influence the association between PRL and SLE. Three forms of PRL are found in the circulation, including monomeric PRL, dimeric PRL, and macro-PRL, being the latter two biologically inactive 84 . Routine PRL assays cannot distinguish between monomeric PRL and macro-PRL 85 , and it is, therefore, possible that hyperprolactinemia found in different studies addressing the association between circulating PRL and SLE vary with respect to the concentration of monomeric PRL that contributes to increased PRL levels. Therefore, hyperprolactinemia may not reflect increased levels of biologically active PRL. Indeed, two studies included in this review found that free (monomeric) PRL, but not total PRL levels, were associated with SLE activity 12 , 53 . This systematic review has some limitations that should be considered when interpreting our findings. The studies addressing circulating PRL levels in SLE were overall small and varied in the characteristics of the participants. Many studies included pre and postmenopausal women and men and did not present data according to sex and menopausal status. Therefore, we could not conduct subgroup analysis according to these variables. It is, hence, unknown whether the magnitude of the association between PRL and SLE and its activity varies with age, gender, and menopausal status in women. Moreover, the time since SLE diagnosis varied between subjects in the included studies, but we could not examine its effect on the association between serum PRL and SLE and its activity. In addition, the systematic review addressing the effect of dopaminergic agonists in SLE activity was limited by the impossibility of conducting a meta-analysis due to the heterogeneity of the included studies, such as the type of dopaminergic agonist assessed, the type of population, and the study design. Moreover, the studies were overall small, with few individuals included. Notwithstanding, the findings from our review raise questions that should be addressed in future studies, including if dopaminergic agonists would benefit individuals with severe SLE as adjunctive therapy or how they would compare to standard treatment in milder disease. Moreover, whether the effects of dopaminergic agonists solely dependent upon PRL suppression and, if so, what the optimal level of suppression would be is currently unknown. It should also be pointed out that cabergoline, a potent and long-acting dopaminergic agonist 86 , was not studied in individuals with SLE. Due to its prolonged half-life, cabergoline has greater efficacy in suppressing PRL secretion, fewer adverse effects, and more convenient dosing compared with bromocriptine and quinagolide, which would increase tolerability and compliance 87 . In conclusion, this systematic review and meta-analysis indicates hyperprolactinemia rates and serum PRL levels are significantly higher among individuals with SLE compared with controls and that serum PRL is moderately correlated with disease activity. Moreover, adjunctive treatment with the dopaminergic agonists bromocriptine and quinagolide is effective in decreasing SLE activity in individuals without rapidly progressive or life-threatening disease. The findings from this systematic review also raise several points that should be addressed in future studies to improve our understanding of the link between PRL and SLE, including whether the association between circulating PRL and SLE varies with age, sex, menopausal status, time since SLE diagnosis, persistent versus sporadic serum PRL elevation, or the increase of different circulating forms of PRL. Given the correlation between PRL and SLE activity, it would also be interesting to explore the role of PRL as a biomarker of disease activity by examining the impact of SLE therapy on circulating PRL in prospective studies. Moreover, it would be important to reassess the effect of dopaminergic agonists on SLE activity, given the availability of cabergoline, which has a more favorable tolerability profile. Declarations Conflict of interest: the authors declare no conflict of interest. Funding: this work had no funding. Author Contribution A.A.C.: Conceptualization, Methodology, Data curation, Writing: original draft preparation.L.F.C.: Conceptualization, Methodology, Data curation, Writing: original draft preparation.C.L.L.: Data curation; Writing: Reviewing and Editing.L.D.C.M.: Conceptualization, Methodology, Data curation, Writing: Reviewing and Editing.L.A.C.R.M: Conceptualization, Methodology, Data curation, Writing: Reviewing and Editing.A.A.A.: Conceptualization, Methodology, Data curation, Writing: Reviewing and Editing. Acknowledgement We are thankful to Cinthia Gabriel Meireles, Licia Maria Henrique da Mota, and Luciana Ansaneli Naves for the intellectual discussions that contributed to the work. Data Availability All data generated or analyzed during this study are included in the manuscript. References Lisnevskaia, L., Murphy, G. & Isenberg, D. Systemic lupus erythematosus. Lancet 384, 1878–1888 (2014). Crow, M. K. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4477148","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":313779858,"identity":"1ee45d9b-6bbe-4a55-a3ca-85fee248e846","order_by":0,"name":"Álida Alves dos Santos","email":"","orcid":"","institution":"University of Brasília","correspondingAuthor":false,"prefix":"","firstName":"Álida","middleName":"Alves dos","lastName":"Santos","suffix":""},{"id":313779859,"identity":"f9083e19-b86d-4403-974f-aaf13efef3dd","order_by":1,"name":"Lucas Faria de Castro","email":"","orcid":"","institution":"University of Brasília","correspondingAuthor":false,"prefix":"","firstName":"Lucas","middleName":"Faria","lastName":"de Castro","suffix":""},{"id":313779860,"identity":"e40de502-cece-44fc-b0ba-ca8d13b2f909","order_by":2,"name":"Caroline Lourenço de Lima","email":"","orcid":"","institution":"University of Brasília","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"Lourenço","lastName":"de Lima","suffix":""},{"id":313779861,"identity":"763afa46-b1e8-497b-8620-afafe5bc57ef","order_by":3,"name":"Lucilia Domingues Casulari da Motta","email":"","orcid":"","institution":"University of Brasília","correspondingAuthor":false,"prefix":"","firstName":"Lucilia","middleName":"Domingues Casulari da","lastName":"Motta","suffix":""},{"id":313779862,"identity":"dec76209-53ec-43d4-860a-882d148d07c7","order_by":4,"name":"Luiz Augusto Casulari Roxo da Motta","email":"","orcid":"","institution":"University of Brasília","correspondingAuthor":false,"prefix":"","firstName":"Luiz","middleName":"Augusto Casulari Roxo da","lastName":"Motta","suffix":""},{"id":313779863,"identity":"825501a0-d461-4624-b2a6-c2c91dca16a7","order_by":5,"name":"Angélica Amato","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYLCCBwZQxgcGhgQGCWK0JIC1MDMwziBeCwNECzMPMVr4Z7dffJBQYCev237+4GPbtjt5DNK9D/BqkbhzptggwSDZcNuZZGbj3LZnxQwyxw3wamG4kZMmkWBwgHHbgWQ26dy2w4kNEmn4dcjfyEn/AdRiv+38YzZpS2K0GNxIPwYMsQOJ224AbWEkRovhjRxmoMOSk7fdeGxs2HPucDGbzDH8WuRupD/88OGPne2284kPH/woO5zHL92GXwsDAw9a+LAR0sDAwP6AsJpRMApGwSgY2QAAAv5KOL8L3y8AAAAASUVORK5CYII=","orcid":"","institution":"University of Brasília","correspondingAuthor":true,"prefix":"","firstName":"Angélica","middleName":"","lastName":"Amato","suffix":""}],"badges":[],"createdAt":"2024-05-25 14:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4477148/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4477148/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-74749-y","type":"published","date":"2024-12-03T15:58:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58385605,"identity":"98114d38-128e-4119-9dba-98b7e5d32ef4","added_by":"auto","created_at":"2024-06-14 18:41:03","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":252461,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of literature search and study selection for the first review question (‘Are circulating PRL levels higher in subjects with SLE compared with healthy controls and correlated with SLE activity’?). Adapted from\u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e","description":"","filename":"Figure1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4477148/v1/a8bb12adaedfcd7ec002f155.jpeg"},{"id":58385604,"identity":"65abf7c2-4bde-40ae-a10c-3c3bff6ba232","added_by":"auto","created_at":"2024-06-14 18:41:03","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":239833,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of literature search and study selection for the second review question (‘Does treatment with dopaminergic agonists affect activity?’). Adapted from\u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e","description":"","filename":"Figure2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4477148/v1/ce73f771abbcf0776fb107b1.jpeg"},{"id":58385606,"identity":"27afc701-69c5-4f3d-a5bc-cc44fbc837fb","added_by":"auto","created_at":"2024-06-14 18:41:03","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":528656,"visible":true,"origin":"","legend":"\u003cp\u003eCirculating prolactin levels in systemic lupus erythematosus. (A) Association between hyperprolactinemia and the likelihood of systemic lupus erythematosus, and (B) circulating prolactin levels in subjects with systemic lupus erythematosus and healthy controls. CI: confidence interval; SD: standard deviation; SLE: systemic lupus erythematosus.\u003c/p\u003e","description":"","filename":"Figure3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4477148/v1/938a7d7ab1bde73c029abe5f.jpeg"},{"id":58387406,"identity":"0e68bf94-56c3-4840-aa7b-df4f59682f09","added_by":"auto","created_at":"2024-06-14 18:49:03","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":399971,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between circulating prolactin levels and systemic lupus erythematosus activity. (A) Association between hyperprolactinemia and systemic lupus erythematosus assessed by the SLEDAI, according to the SLEDAI cutoff used to define disease activity. (B) Correlation between circulating prolactin levels and SLE activity assessed by the SLEDAI. CI: confidence interval; SLE: systemic lupus erythematosus.\u003c/p\u003e","description":"","filename":"Figure4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4477148/v1/ec9ebf4affbd601f00bc3e2f.jpeg"},{"id":70965504,"identity":"441aa3b0-35bc-49bc-a6a0-d4ba6678645b","added_by":"auto","created_at":"2024-12-09 16:20:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2924477,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4477148/v1/4af2df96-7a19-494c-a44a-a3fc2ad57b3b.pdf"},{"id":58385608,"identity":"e26cbcf3-d492-4044-a078-51bf36f2963d","added_by":"auto","created_at":"2024-06-14 18:41:03","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":971190,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-4477148/v1/6933ba55a200830db48299f1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Circulating prolactin levels and the effect of dopaminergic agonists in systemic lupus erythematosus: a systematic review and meta-analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSystemic lupus erythematosus (SLE) is a challenging autoimmune disease characterized by diverse clinical manifestations virtually affecting any organ system and with varied severity, ranging from mild and restricted skin involvement to life-threatening vital organ impairment\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The mechanisms underlying immune dysfunction in SLE are complex and involve multiple molecular pathways\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Significant advances in the understanding of SLE pathogenesis over the last decade have highlighted that various genetic, epigenetic, environmental, and hormonal factors interact to alter immune function and lead to autoimmunity and inflammation\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSimilarly to other autoimmune diseases, SLE is significantly more prevalent in women, with a female-to-male ratio ranging from 8:1 to 15:1\u003csup\u003e3,4\u003c/sup\u003e. The latter difference is more pronounced during reproductive age, and SLE activity indicated by disease flares is well-known to increase in pregnancy \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e and with estrogen-containing therapies\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The latter aspects suggest that hormonal influences such as sex steroids and prolactin may be involved in its pathophysiology and clinical course.\u003c/p\u003e \u003cp\u003eProlactin (PRL) is a polypeptide encoded by the PRL gene on chromosome 6 in humans. It is synthesized and secreted by lactotroph cells in the anterior hypophysis and by a myriad of extra-hypophysial sites, such as lymphocytes, ovary, prostate, and adipose tissue, in addition to having many different targets\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. PRL is well-known for its critical role in stimulating the proliferation and differentiation of mammary cells required for lactation. There is also increasing evidence that PRL has pleiotropic functions, affecting metabolic homeostasis, bone physiology, skin and hair follicles, maternal care, adrenal function, immunity, and inflammatory response\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe role of PRL in modulating both innate and acquired immunity raises the question of whether it could be involved in the pathogenesis of autoimmune diseases\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Data from preclinical and clinical research indicate that PRL may affect immune function and the clinical phenotype in SLE. It has been shown to impact autoantigen presentation, interfere with the activity of regulatory T cells, and affect B cell tolerance, the production of cytokines, and neutrophil, macrophage, and dendritic cell function\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Moreover, hyperprolactinemia is reported in 20 to 30% of subjects with SLE\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, and serum PRL levels were associated with the occurrence of neuropsychiatric, renal, cutaneous, and articular manifestations\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, in addition to anti-dsDNA positivity and higher scores of disease activity\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, the mechanisms underlying higher prolactin levels in SLE are not clear, but there is evidence indicating multiple sources, such as increased production by lymphocytes, the stimulatory action of inflammatory cytokines on lactotrophs to increase pituitary PRL secretion, and genetic factors leading to upregulated PRL gene expression\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt is noteworthy, however, that the association between circulating PRL levels and SLE activity is not consistent between different studies. This may be accounted for the heterogeneity in study participants between different studies and the different methods to determine serum prolactin levels or disease activity\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In this setting, we conducted a systematic review and meta-analysis to investigate circulating PRL levels in subjects with SLE compared with healthy controls and examine the correlation between PRL levels and SLE activity. In addition, as a proof of concept for the biologically plausible role of PRL in modulating SLE activity, we conducted a systematic review of clinical trials to investigate the effect of dopamine agonists on SLE activity.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eProtocol and registration\u003c/p\u003e \u003cp\u003eThis systematic review and meta-analysis was registered in the PROSPERO \u003cem\u003e(International Prospective Register of Systematic Reviews)\u003c/em\u003e database (CRD42021237156). We followed the recommendations from the Preferred Reporting Items for Systematic Review and Meta-Analysis (Appendix A) \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eand the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSearch strategy, study selection, and data extraction\u003c/p\u003e \u003cp\u003eThe study questions of the review were created using the PECOS/PICOS acronym (population, exposure/intervention, comparison, outcome, and type of study). For the first review question, whether circulating PRL levels were higher in subjects with SLE compared with healthy controls and were correlated with SLE activity, P was \u0026lsquo;children, men, and nonpregnant and nonlactating women with SLE,\u0026rsquo; E was \u0026lsquo;circulating PRL concentration,\u0026rsquo; C was \u0026lsquo;healthy subjects\u0026rsquo; for case-control studies, O was \u0026lsquo;disease activity assessed by any score,\u0026rsquo; and S was \u0026lsquo;cross-sectional or case-control studies.\u0026rsquo; Therefore, we searched for studies (i) comparing circulating PRL concentration between subjects with SLE and healthy controls, (ii) comparing the frequency of hyperprolactinemia between subjects with SLE and healthy controls, and/or (iii) addressing the association between circulating PRL levels and SLE activity assessed by a validated score.\u003c/p\u003e \u003cp\u003eFor the second review question, whether treatment with dopaminergic agonists affected SLE activity, P was \u0026lsquo;subjects with SLE,\u0026rsquo; I was \u0026lsquo;dopamine agonists,\u0026rsquo; C was \u0026lsquo;subjects with SLE not treated with dopamine agonists,\u0026rsquo; O was \u0026lsquo;disease activity assessed by any score,\u0026rsquo; and S was \u0026lsquo;clinical trials or case-control studies.\u0026rsquo; The inclusion criteria were clinical trials or case-control studies examining the effect of any dopamine agonist on indicators of SLE activity.\u003c/p\u003e \u003cp\u003eReviews, case reports, case series, book chapters, and conference abstracts were excluded. Studies involving pregnant women were also excluded.\u003c/p\u003e \u003cp\u003eWe searched PubMed, Scopus, Web of Science, Cochrane, Embase, and Google Scholar from inception to July 27, 2023, using search terms related to the population (SLE), the exposure (prolactin) or intervention (dopaminergic agonists), and the outcome (disease activity), considering studies published in English, Portuguese, or Spanish. Only the first 100 retrieved records from Google Scholar were considered. The search strategy is presented in Appendices B and C.\u003c/p\u003e \u003cp\u003eWe also conducted manual searches across reference lists of the included studies. A reference management software (Endnote version 9) was used to collect the references and exclude duplicate studies. Study selection was conducted in two phases. First, two reviewers (A.A.S. e L.F.C.) independently screened the titles and abstracts to select eligible studies. Secondly, the same reviewers independently read the full-text version of the selected studies and applied the inclusion and exclusion criteria. In each phase, disagreements between the two reviewers were resolved by discussion with a third reviewer (A.A.A.).\u003c/p\u003e \u003cp\u003eFor the first review question, the authors, year of publication, country, study design, sample size, age range, sex, method to determine circulating PRL levels, method for SLE activity assessment, and main findings were extracted from the studies. The main findings were extracted considering the following outcomes: (i) hyperprolactinemia rate in subjects with SLE and healthy controls, (ii) circulating PRL levels in subjects with SLE and healthy controls, (iii) hyperprolactinemia rate in subjects with active versus inactive SLE, (iv) circulating PRL levels in subjects with active versus inactive SLE, and (v) the correlation between circulating PRL levels in subjects with SLE and disease activity.\u003c/p\u003e \u003cp\u003eFor the second review question, the authors, year of publication, sample size, age range, sex, type of dopamine agonist, method for SLE activity assessment, main findings, and study design were extracted from the included studies.\u003c/p\u003e \u003cp\u003eRisk of bias between studies\u003c/p\u003e \u003cp\u003eThe risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Checklist \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e for cross-sectional (Appendix D) and case-control studies (Appendix E), for the first review question, and quasi-experimental trials (Appendix F) and randomized clinical trials (Appendix G), for the second review question. The assessment was independently conducted by two reviewers (A.A.S. and L.F.C.) following agreement on scoring decisions. Any disagreement was resolved by discussion with a third reviewer (A.A.A.). A high risk of bias was considered when the study reached 49% or less of the score \u0026lsquo;yes,\u0026rsquo; a moderate risk of bias when it reached 50 to 69% of the score \u0026lsquo;yes,\u0026rsquo; and a low risk of bias when it reached 70% or more of the score \u0026lsquo;yes\u0026rsquo;.\u003c/p\u003e \u003cp\u003eResults of individual studies\u003c/p\u003e \u003cp\u003eThe data extracted from individual studies were presented in a table format, with their main findings described.\u003c/p\u003e \u003cp\u003eSynthesis of results (meta-analysis)\u003c/p\u003e \u003cp\u003eWe pooled the following data from individual studies, using random-effect meta-analysis: (i) hyperprolactinemia rate in subjects with SLE and healthy controls, (ii) circulating PRL levels in subjects with SLE and healthy controls, (iii) hyperprolactinemia rate in subjects with active or inactive SLE, and (iv) the correlation between circulating PRL levels in subjects with SLE and disease activity. Data on hyperprolactinemia rate in subjects with SLE and healthy controls were summarized as odds ratio with 95% confidence interval (95%CI), and data on circulating PRL levels in subjects with SLE and healthy controls were reported standardized mean difference with 95% confidence interval. Circulating PRL levels assessed in mIU/L were converted into ng/mL dividing the results by 21\u003csup\u003e15\u003c/sup\u003e. We did not pool data on circulating PRL levels in subjects with active and inactive SLE since most studies only described mean or median values without the error, and some studies did not report the number of subjects with active or inactive disease.\u003c/p\u003e \u003cp\u003eTo assess the correlation between SLEDAI and serum PRL, a meta-analysis of the Pearson correlation coefficient extracted from each study was performed using the random-effects model\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. If study values for the Pearson correlation coefficient (\u003cem\u003er\u003c/em\u003e) were not available, the Spearman correlation (\u003cem\u003ers\u003c/em\u003e) coefficient were used to estimate \u003cem\u003er\u003c/em\u003e values using the following formula: \u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2 \u0026times; sin(\u003cem\u003ers\u003c/em\u003e\u0026times;p/6)\u003csup\u003e22\u003c/sup\u003e. Correlation coefficient values were converted by Fisher's r-to-z transformation to obtain approximately normally distributed z values and the related 95% confidence interval.\u003c/p\u003e \u003cp\u003eStatistical heterogeneity across studies was examined using the I\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e statistic, and publication bias (small-study effect) was assessed by examining the funnel plot. Statistical significance was considered when at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The analyses were conducted using RevMan software 5.4 and STATA 16.0 software package.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFor the first review question, whether circulating PRL levels were higher in subjects with SLE compared with healthy controls and were correlated with SLE activity, our search retrieved 220 studies, of which 55 were selected for full-text assessment. Fifty-five studies met our inclusion criteria, and ten were excluded (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Appendix H).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor the second review question, whether treatment with dopaminergic agonists affected SLE activity, we identified 468 studies, and eight were selected for full-text assessment (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Three studies were excluded: one was excluded because it involved dopamine agonist administration during pregnancy\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, and two were excluded because they did not report SLEDAI scores following dopamine agonist treatment\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCharacteristics of studies examining circulating prolactin concentration in systemic lupus erythematosus\u003c/p\u003e \u003cp\u003eSeventeen studies were conducted in Asia\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan additionalcitationids=\"CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, 12 in America\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan additionalcitationids=\"CR43 CR44 CR45 CR46 CR47 CR48 CR49 CR50 CR51\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e, 11 in Europe\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan additionalcitationids=\"CR54 CR55 CR56 CR57 CR58 CR59 CR60 CR61\" citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e, and five in Africa\u003csup\u003e\u003cspan additionalcitationids=\"CR64 CR65 CR66\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. Fifteen studies had a cross-sectional design and examined the association between circulating PRL levels and SLE activity, whereas 30 were case-control studies comparing circulating PRL levels between subjects with SLE and healthy controls and/or investigating the association between circulating PRL levels and SLE activity. Sample sizes ranged from 19 to 259 subjects, and most studies described as exclusion criteria conditions affecting circulating PRL levels, such as pregnancy, lactation, renal and hepatic failure, or drugs. The methods to determine circulating PRL concentration varied between studies, and most presented total PRL levels; three also reported free PRL levels\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e. SLE activity was most frequently assessed by the SLE Disease Activity Index (SLEDAI) score and less frequently by the European Consensus Lupus Activity Measure (ECLAM) index\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e,\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e, the Systemic Lupus Activity Measure (SLAM) index\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e, Duke Severity of Illness (DUSOI) score\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e, or the combination of signs, symptoms, and serologic markers\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. Study characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies (n\u0026thinsp;=\u0026thinsp;45).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthors, year\u003c/p\u003e \u003cp\u003eCountry\u003c/p\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePRL assessment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum prolactin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRL and disease activity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eConclusion\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLavalle et al., 1987\u003c/p\u003e \u003cp\u003eMexico\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;8 (male, mean 28.1 y, range 19\u0026ndash;39 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;11 (male, mean 28.5 y, range 25\u0026ndash;40 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: active SLE, renal/liver failure, hypothyroidism, pituitary adenoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (assay cutoff NR)\u003c/p\u003e \u003cp\u003eSLE: 7/8\u003c/p\u003e \u003cp\u003eControls: 0/11\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 16 \u0026plusmn; 3\u003c/p\u003e \u003cp\u003eControls: 4.3 \u0026plusmn; 0.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFolomeev et al., 1990\u003c/p\u003e \u003cp\u003eRussia\u003c/p\u003e \u003cp\u003eCase control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;29 (male)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10 (male)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (mU/mL; mean \u0026plusmn; SEM)\u003c/p\u003e \u003cp\u003eSLE: 358.10 \u0026plusmn; 67.35\u003c/p\u003e \u003cp\u003eControls: 135.75 \u0026plusmn; 10.319\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJara et al., 1992\u003c/p\u003e \u003cp\u003eUS\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;45\u003c/p\u003e \u003cp\u003eHealthy controls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;28 (12 male, 16 female; range 20\u0026ndash;65 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;20 ng/mL):\u003c/p\u003e \u003cp\u003eSLE: 10/45\u003c/p\u003e \u003cp\u003eControl: 0/28\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean, range)\u003c/p\u003e \u003cp\u003eSLE: 17.2, 3.6\u0026ndash;188\u003c/p\u003e \u003cp\u003eControls: 8.4, 2.5\u0026ndash;17.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.369\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSequeira et al., 1993\u003c/p\u003e \u003cp\u003eUK\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;14 (male; mean 36 \u0026plusmn; 12.2 y, range 22\u0026ndash;67 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;17 (male; mean 31 \u0026plusmn; 4.0 y, range 27\u0026ndash;40 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: hypogonadism, previous therapy with cyclophosphamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eETA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;360 mIU/L)\u003c/p\u003e \u003cp\u003eSLE: 1/14\u003c/p\u003e \u003cp\u003eControls: 0/17\u003c/p\u003e \u003cp\u003eSerum PRL (mIU/L; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 171 \u0026plusmn; 107\u003c/p\u003e \u003cp\u003eControls: 167 \u0026plusmn; 161\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuskila et al., 1996\u003c/p\u003e \u003cp\u003eIsrael\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;63 (4 male, 59 female; mean 31.6 y, range 16\u0026ndash;68 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, abnormal thyroid function, abnormal liver function, renal failure, drugs interfering with PRL serum levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = -0.186\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEl-Garf et al., 1996\u003c/p\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;33 (5 male, 28 female; mean 10.9 y, range 6\u0026ndash;13 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;20 (4 male, 16 female; mean 11.6 y, range 7\u0026ndash;13 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: sellar abnormalities, visual field and fundi abnormalities, drugs interfering with PRL serum levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;25.53 ng/mL)\u003c/p\u003e \u003cp\u003eSLE: 3/33\u003c/p\u003e \u003cp\u003eControls: 0/20\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 14.42 \u0026plusmn; 7.5\u003c/p\u003e \u003cp\u003eControls: 12.69 \u0026plusmn; 6.42\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLAM\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.089\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not higher in subjects with SLE compared to healthy controls and were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOstendorf et al., 1996\u003c/p\u003e \u003cp\u003eGermany\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;182 (14 male, 168 female; mean 41 y, range 16\u0026ndash;72 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR (none of the included subjects were taking drugs interfering with PRL serum levels)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;15 ng/mL for male and \u0026gt;\u0026thinsp;20 ng/mL for female): 4/182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDAI\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u0026thinsp;=\u0026thinsp;NR\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRovensky et al., 1997\u003c/p\u003e \u003cp\u003eSlovakia\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;35 (4 male, 31 female, mean 45 \u0026plusmn; 2 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, hypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eECLAM\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.201\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerreira et al., 1998\u003c/p\u003e \u003cp\u003ePortugal\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24 (1 male, 23 female; mean 42.5 \u0026plusmn; 14.0 y, range 17\u0026ndash;65 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;15 (1 male, 14 female; mean 39.9 \u0026plusmn; 11.2 y, range 27\u0026ndash;64 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMEIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;20 ng/mL):\u003c/p\u003e \u003cp\u003eSLE: 9/24\u003c/p\u003e \u003cp\u003eControl: 2/15\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 19.3 \u0026plusmn; 9.2\u003c/p\u003e \u003cp\u003eControls: 10.2 \u0026plusmn; 5.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSigns, symptoms, and serologic markers\u003c/p\u003e \u003cp\u003eInactive: 18.2 \u0026plusmn; 63.5\u003c/p\u003e \u003cp\u003eActive: 11.9 \u0026plusmn; 36.8\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls but were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJimena et al., 1998\u003c/p\u003e \u003cp\u003eUK\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;36 (female; 32.3 \u0026plusmn; 8.5 y)\u003c/p\u003e \u003cp\u003eHealthy controls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;20 (female; mean 32.2 \u0026plusmn; 9.3 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, renal/hepatic failure, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;20 ng/mL)\u003c/p\u003e \u003cp\u003eSLE: 10/36\u003c/p\u003e \u003cp\u003eControls: 0/20\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD, and range)\u003c/p\u003e \u003cp\u003eSLE: 17.1 \u0026plusmn; 12.9, 4\u0026ndash;36\u003c/p\u003e \u003cp\u003eControls: 9.9 \u0026plusmn; 3.5, 5-16.6\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;10)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL mean \u0026plusmn; SD, and range)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;10: 14.8 \u0026plusmn; 6.9\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10: 21.1 \u0026plusmn; 4.8\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.09\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.049\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls but were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMok et al., 1998\u003c/p\u003e \u003cp\u003eHong Kong\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;31 (male; mean 39.0 \u0026plusmn; 2.7 y, range 18\u0026ndash;71 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;31 (male; mean 39.3 \u0026plusmn; 2.4 y, range 20\u0026ndash;71 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: prolactinoma, renal failure, chest wall lesions, hypothyroidism, drugs interfering with serum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (mIU/L, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE 230 \u0026plusmn; 14\u003c/p\u003e \u003cp\u003eControls: 194 \u0026plusmn; 17\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;5)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (IU/mL mean)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 227\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5: 234\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.63\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.24\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not higher in subjects with SLE compared to healthy controls and were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChang et al., 1999\u003c/p\u003e \u003cp\u003eChina\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;16 (male, mean 26 \u0026plusmn; 9 y, range 19\u0026ndash;46 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;20 (male, mean 30 \u0026plusmn; 4 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL)\u003c/p\u003e \u003cp\u003eSLE: 17.6 \u0026plusmn; 10.6\u003c/p\u003e \u003cp\u003eControls: 6.6 \u0026plusmn; 2.8\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMok et al., 2000\u003c/p\u003e \u003cp\u003eHong Kong\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;35 (male, mean 40.1 \u0026plusmn; 2.3 y, range 17\u0026ndash;71 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;33 (male, mean 38.7 \u0026plusmn; 2.2 y, range 19\u0026ndash;71 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: hypogonadism, therapy with cyclophosphamide, renal failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (mIU/L, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE 220.4 \u0026plusmn; 15.1\u003c/p\u003e \u003cp\u003eControls: 190.6 \u0026plusmn; 15.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;2)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;2: 235 \u0026plusmn; 23\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;2: 219 \u0026plusmn; 20\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.85\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.27\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not higher in subjects with SLE compared to healthy controls and were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCruz et al., 2001\u003c/p\u003e \u003cp\u003eMexico\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;35 (5 male, 30 female; mean 34 \u0026plusmn; 4 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10 (2 male, 8 female; mean 34 \u0026plusmn; 4 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, renal/hepatic failure, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA, ELISA, and BA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SEM)\u003c/p\u003e \u003cp\u003eRIA\u003c/p\u003e \u003cp\u003eSLE: 12.2 \u0026plusmn; 0.9\u003c/p\u003e \u003cp\u003eControls: 10.2 \u0026plusmn; 1.7\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eELISA\u003c/p\u003e \u003cp\u003eSLE: 43.6 \u0026plusmn; 4.8\u003c/p\u003e \u003cp\u003eControls: 21.4 \u0026plusmn; 7.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eBA\u003c/p\u003e \u003cp\u003eSLE: 44 \u0026plusmn; 4.3\u003c/p\u003e \u003cp\u003eControls: 37.3 \u0026plusmn; 4.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels assessed by ELISA but not RIA or BA were higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHrycek et al., 2001\u003c/p\u003e \u003cp\u003ePoland\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;20 (5 male, 15 female; mean 36.5 y, range 31\u0026ndash;44 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;17 (4 male, 13 female; mean 36.7 y, range 30\u0026ndash;43 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, renal/hepatic failure, drugs interfering with serum PRL levels, rapidly progressive SLE and life-threatening SLE complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (mIU/L)\u003c/p\u003e \u003cp\u003eSLE: 355.41 \u0026plusmn; 235.37\u003c/p\u003e \u003cp\u003eControls: 230.53 \u0026plusmn; 159.35\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJacobi et al., 2001\u003c/p\u003e \u003cp\u003eGermany\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;60 (8 male, 52 female; mean 35.6 y)\u003c/p\u003e \u003cp\u003eHealthy controls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;47 (17 male, 30 female; mean 32.9 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, prolactinoma, hypothyroidism, renal failure, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;20 ng/mL):\u003c/p\u003e \u003cp\u003eSLE: 17/60\u003c/p\u003e \u003cp\u003eControl: 0/47\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE:\u003c/p\u003e \u003cp\u003eAll: 17.4 \u0026plusmn; 15.1\u003c/p\u003e \u003cp\u003eMale: 12.8 \u0026plusmn; 7.5\u003c/p\u003e \u003cp\u003ePostmenopausal female: 12.7 \u0026plusmn; 7.0\u003c/p\u003e \u003cp\u003ePremenopausal female: 20.0 \u0026plusmn; 17.5\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003eAll: 6.3 \u0026plusmn; 3.2\u003c/p\u003e \u003cp\u003eMale: 5.5 \u0026plusmn; 3.2\u003c/p\u003e \u003cp\u003ePremenopausal female: 6.7 \u0026plusmn; 3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eECLAM (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eSerum PRL according to ECLAM (ng/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 12.8 \u0026plusmn; 9.3\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 22.1 \u0026plusmn; 18.2\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.003\u003c/p\u003e \u003cp\u003eCorrelation PRL and ECLAM-score\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.54\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePacilio et al., 2001\u003c/p\u003e \u003cp\u003eItaly\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;78 (5 male, 73 female; median 31 y, range 16\u0026ndash;71 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;20 (2 male, 18 female; median 28 y, range 19\u0026ndash;60 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: disorders and drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003cp\u003eBA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;20 ng/mL):\u003c/p\u003e \u003cp\u003eSLE: 21/78 (IRMA), 31/78 (BA)\u003c/p\u003e \u003cp\u003eControls: 0/20\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD, range)\u003c/p\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003cp\u003eSLE: 15.2 \u0026plusmn; 9.1, 2.2\u0026ndash;51.2\u003c/p\u003e \u003cp\u003eControls: 8.9 \u0026plusmn; 3.2, 3.4\u0026ndash;16.2\u003c/p\u003e \u003cp\u003eBA:\u003c/p\u003e \u003cp\u003eSLE: 22.2 \u0026plusmn; 14.6, 4.2\u0026ndash;84\u003c/p\u003e \u003cp\u003eControls: 12.8 \u0026plusmn; 2.7, 3.2\u0026ndash;18.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL mean, range)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;10: 8.65, 4\u0026ndash;14 (IRMA); 12.5, 3.6\u0026ndash;20.6\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10: 19.9, 6.3\u0026ndash;51.2; 31.0, 12.4\u0026ndash;72.8 (BA)\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001 (IRMA and BA)\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;44\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003eBA\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.41\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKramer et al., 2005\u003c/p\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;26 (1 male, 25 female; mean 35.4 \u0026plusmn; 11.7 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;28 (2 male, 26 female, mean 49.6 \u0026plusmn; 12.9 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: hypothyroidism, pregnancy, lactation, kidney/liver failure, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 21.3 \u0026plusmn; 12.6\u003c/p\u003e \u003cp\u003eControls: 12.5 \u0026plusmn; 6.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHrycek et al., 2007\u003c/p\u003e \u003cp\u003ePoland\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25 (4 male, 21 female; mean 43.37 \u0026plusmn; 11.85 y, range 18\u0026ndash;73 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;24 (4 male, 21 female; mean 52.2 \u0026plusmn; 16.18 y, range 18\u0026ndash;78 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, MoMorenal/hepatic failure, drugs interfering with serum PRL levels, rapidly progressive SLE and life-threatening SLE complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 16.2 \u0026plusmn; 10.6\u003c/p\u003e \u003cp\u003eControls: 8.55 \u0026plusmn; 4.97\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRastin et al., 2007\u003c/p\u003e \u003cp\u003eIran\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;38 (10 male, 28 female; mean 27 y, range 16\u0026ndash;47 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;20 (10 male, 10 female; mean 28 y, range 18\u0026ndash;42 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (mIU/L, mean \u0026plusmn; SD, all)\u003c/p\u003e \u003cp\u003eSLE: 24.4 \u0026plusmn; 3.1\u003c/p\u003e \u003cp\u003eControls: 11.2 \u0026plusmn; 1.2\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eSerum PRL (mIU/L, mean \u0026plusmn; SD, female)\u003c/p\u003e \u003cp\u003eSLE: 25.08 \u0026plusmn; 4.3\u003c/p\u003e \u003cp\u003eControls: 13.7 \u0026plusmn; 2.03\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eSerum PRL (mIU/L, mean \u0026plusmn; SD, male)\u003c/p\u003e \u003cp\u003eSLE: 23.0 \u0026plusmn; 4.2\u003c/p\u003e \u003cp\u003eControls: 8.6 \u0026plusmn; 0.74\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u0026oacute;mez-P\u0026eacute;rez et al., 2003\u003c/p\u003e \u003cp\u003eVenezuela\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;18 (female; mean 30 \u0026plusmn; 10 y, range 18\u0026ndash;48 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, renal failure, other causes of hyperprolactinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 10.84 \u0026plusmn; 3.64\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 37.95 \u0026plusmn; 33.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVera-Lastra et al., 2003\u003c/p\u003e \u003cp\u003eUS\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;43 (female)\u003c/p\u003e \u003cp\u003eNo renal involvement: mean 27.7 \u0026plusmn; 11.1 y\u003c/p\u003e \u003cp\u003eRenal involvement: mean 28.6 \u0026plusmn; 5.2 y\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;36 (female; mean 28.3 \u0026plusmn; 10.3 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, renal/hepatic failure, hypothyroidism, seizures, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 23.55 \u0026plusmn; 5.88\u003c/p\u003e \u003cp\u003eControls: 6.43 \u0026plusmn; 2.24\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI (linear regression)\u003c/p\u003e \u003cp\u003er\u0026thinsp;=\u0026thinsp;0.4946\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0007\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDai et al., 2006\u003c/p\u003e \u003cp\u003eUS\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;80 (9 male, 71 female; mean 31.8y, range 12\u0026ndash;58 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25 (6 male, 19 female, mean 34.8 \u0026plusmn; 13.0 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, prolactinoma, hypothyroidism, renal failure, liver disease, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;480 \u0026micro;IU/mL in male and 650 \u0026micro;IU/mL in female):\u003c/p\u003e \u003cp\u003eSLE: 32/80\u003c/p\u003e \u003cp\u003eControls: 0/25\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003eSerum PRL (\u0026micro;IU/mL; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE (active): 718 \u0026plusmn; 274 \u0026micro;IU/mL\u003c/p\u003e \u003cp\u003eSLE (inactive): 476 \u0026plusmn; 156 \u0026micro;IU/mL\u003c/p\u003e \u003cp\u003eControls: 274 \u0026plusmn; 135 \u0026micro;IU/mL\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;9)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (\u0026micro;IU/mL; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;9: 718 \u0026plusmn; 274 \u0026micro;IU/mL\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;9: 476 \u0026plusmn; 156 \u0026micro;IU/mL\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.638\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaghighi et al., 2006\u003c/p\u003e \u003cp\u003eIran\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;35 (4 male, 31 female; mean 26.7 y, range 9\u0026ndash;54 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;60 (8 male, 52 female, mean 28.3 y, range 13\u0026ndash;48 y)\u003c/p\u003e \u003cp\u003eExclusion criteria:\u003c/p\u003e \u003cp\u003epregnancy, lactation, renal/hepatic failure, hypothyroidism, seizures, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;721 mIU/L for female and \u0026lt;\u0026thinsp;414 mIU/L for male)\u003c/p\u003e \u003cp\u003eSLE: 10/35\u003c/p\u003e \u003cp\u003eControls: 2/60\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eSerum PRL (mIU/L, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 770 \u0026plusmn; 860\u003c/p\u003e \u003cp\u003eControls: 341 \u0026plusmn; 335\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0078\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u0026thinsp;=\u0026thinsp;NR\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLea\u0026ntilde;os-Miranda et al., 2006\u003c/p\u003e \u003cp\u003eMexico\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;259 (16 male, 243 female; mean 35.5 \u0026plusmn; 11.2 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR (none of the included subjects had obvious causes of hyperprolactinemia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia\u003c/p\u003e \u003cp\u003eFree PRL: 56/259\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; median and range)\u003c/p\u003e \u003cp\u003eTotal PRL: 13.8, 1.2-281.7\u003c/p\u003e \u003cp\u003eFree PRL: 9.8, 1.3-105.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL; median)\u003c/p\u003e \u003cp\u003eTotal PRL\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 20.1 ng/mL\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 22.7 ng/mL\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.53\u003c/p\u003e \u003cp\u003eFree PRL\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 9.3 ng/mL\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 12.6 ng/mL\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003eTotal PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.09\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.15\u003c/p\u003e \u003cp\u003eFree PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.31\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum free but not total PRL levels were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRezaieyazdi et al., 2006\u003c/p\u003e \u003cp\u003eIran\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30 (4 male, 26 female, mean 24.5 y, range 5\u0026ndash;50 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, pituitary adenoma, renal/liver failure, thyroid disorder, drugs that interfere with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;16 ng/mL in male and 25 ng/mL in female):\u003c/p\u003e \u003cp\u003e10/30\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD, range)\u003c/p\u003e \u003cp\u003eAll: 33.8 \u0026plusmn; 19.8, 7\u0026ndash;85\u003c/p\u003e \u003cp\u003eMale: 4.9 \u0026plusmn; 4.9, 13\u0026ndash;23\u003c/p\u003e \u003cp\u003eFemale: 35.6 \u0026plusmn; 20.3, 7\u0026ndash;85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLAM\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLAM\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.675\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u0026aacute;rdenas-Mondrag\u0026oacute;n et al., 2007\u003c/p\u003e \u003cp\u003eFrance\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;98 (5 male, 93 female; mean 33.0 \u0026plusmn; 10.5 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR (none of the included subjects had obvious causes of hyperprolactinemia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL; mean \u0026plusmn; SD or median, range)\u003c/p\u003e \u003cp\u003eTotal PRL\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 19.9 \u0026plusmn; 28.8\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 22.9 \u0026plusmn; 17.4\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.49\u003c/p\u003e \u003cp\u003eFree PRL\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 10.6 \u0026plusmn; 6.0\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 17.9 \u0026plusmn; 18.1\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.008\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003eTotal PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.074\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.47\u003c/p\u003e \u003cp\u003eFree PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.44\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum free but not total PRL levels were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElwakkad et al., 2007\u003c/p\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;12 (2 male, 10 female; mean 15.8 \u0026plusmn; 2.9 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;21 (age and sex-matched)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL; mean \u0026plusmn; SD, range)\u003c/p\u003e \u003cp\u003eSLE: 424.167 \u0026plusmn; 119.58\u003c/p\u003e \u003cp\u003eControls: 284.17 \u0026plusmn; 96.24\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003eTotal PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.975\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJokar et al., 2008\u003c/p\u003e \u003cp\u003eIran\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;90 (7 male, 83 female; mean 27.6 \u0026plusmn; 9.1 y, range 14\u0026ndash;52 y)\u003c/p\u003e \u003cp\u003eExclusion criteria:\u003c/p\u003e \u003cp\u003epregnancy, lactation, menopause, primary amenorrhea, previous history of hysterectomy, oophorectomy, and current use of oral contraceptive agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;28 ng/mL): 9/90\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SD, range): 17.55 \u0026plusmn; 8.4, 6\u0026ndash;48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eHyperprolactinemia according to SLEDAI\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 2/33\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 7/57\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.343\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL; mean)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 17.94\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 8.68\u003c/p\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.563\u003c/p\u003e\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShabanova et al., 2008\u003c/p\u003e \u003cp\u003eRussia\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;94 (female; mean 29.2 \u0026plusmn; 7 y, range 16\u0026ndash;45 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40\u003c/p\u003e \u003cp\u003eExclusion criteria:\u003c/p\u003e \u003cp\u003epregnancy, lactation, menopause, primary amenorrhea, previous history of hysterectomy, oophorectomy, and current use of oral contraceptive agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;726 mIU/mL):\u003c/p\u003e \u003cp\u003eSLE: 9/94\u003c/p\u003e \u003cp\u003eControls: 0/40\u003c/p\u003e \u003cp\u003eSerum PRL (mIU/mL, mean and range):\u003c/p\u003e \u003cp\u003eSLE: 274, 272\u0026ndash;563\u003c/p\u003e \u003cp\u003eControls: 344, 227\u0026ndash;438\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;10)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (mIU/mL; mean and range)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;10: 347, 263\u0026ndash;486\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10: 450, 275\u0026ndash;675\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParaiba et al., 2010\u003c/p\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30 (3 male, 27 female; median 32 y, range 20\u0026ndash;48 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10 (1 male, 9 female; median 31.5 y, range 24\u0026ndash;42 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, prolactinoma, hypothyroidism, renal failure, drugs interfering with PRL serum levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIFMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;14.5 ng/mL):\u003c/p\u003e \u003cp\u003eSLE: 8/30\u003c/p\u003e \u003cp\u003eControls: 0/10\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL, median and range):\u003c/p\u003e \u003cp\u003eSLE: 9.65, 1.9\u0026ndash;38.9\u003c/p\u003e \u003cp\u003eControls: 6.4, 2.4\u0026ndash;10.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eHyperprolactinemia according to SLEDAI\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 1/12\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 7/18\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.02\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL; median and range)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 7.65, 1.9\u0026ndash;15.5\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 10.85, 5-38.9\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eShahin, 2011\u003c/p\u003e \u003cp\u003eSaudi Arabia\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;33 (female; mean 29.3 \u0026plusmn; 9.5 y, range 13\u0026ndash;45 y)\u003c/p\u003e \u003cp\u003eExclusion criteria:\u003c/p\u003e \u003cp\u003erenal and/or hepatic failure, pregnancy, hypothyroidism, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;511 mIU/mL): 10/33\u003c/p\u003e \u003cp\u003eSerum PRL (mIU/mL, mean \u0026plusmn; SD and range): 680.7 \u0026plusmn; 1021.5, 198\u0026ndash;4500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eSerum PRL (mIU/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 331.5 \u0026plusmn; 129.9\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 728.9 \u0026plusmn; 1082\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.09\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOrbach et al., 2012\u003c/p\u003e \u003cp\u003eHungary and Italy\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;256 (31 male, 225 female; median 36.5 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;498 mIU/L in male and 392 mIU/L in female)\u003c/p\u003e \u003cp\u003e45/256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eECLAM (\u0026gt;\u0026thinsp;2, Italy) and SLEDAI (\u0026gt;\u0026thinsp;4, Hungary)\u003c/p\u003e \u003cp\u003eECLAM or SLEDAI not associated with the presence of hyperprolactinemia (data NR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKarimifar et al., 2013\u003c/p\u003e \u003cp\u003eIran\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;60 (female; median 31 y, range 15\u0026ndash;60 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, prolactinoma, hypothyroidism, serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;2 mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;20 ng/mL): 5/60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003eTotal PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.062\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhu et al., 2015\u003c/p\u003e \u003cp\u003eChina\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;47 (5 male, 42 female; mean 34.1 \u0026plusmn; 2.5 y, range 15\u0026ndash;53 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;10 (1 male, 9 female; mean 30 y, range 18\u0026ndash;50 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: subjects with active SLE treated with corticosteroids or immunosuppressants, subjects with inactive SLE treated with prednisone at doses over 5\u0026ndash;15 mg/d, abnormal thyroid function, other autoimmune diseases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (unit NR; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE (active): 14.45 \u0026plusmn; 7.25\u003c/p\u003e \u003cp\u003eSLE (inactive): 11.79 \u0026plusmn; 8.02\u003c/p\u003e \u003cp\u003eControls: 7.08 \u0026plusmn; 6.26\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.01 (SLE vs control)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eHyperprolactinemia according to SLEDAI\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 3/13\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 18/34\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (unit NR; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 11.79 \u0026plusmn; 8.02\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 14.45 \u0026plusmn; 7.25\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls, hyperprolactinemia frequency was higher in subjects with active SLE, serum PRL levels were not different between subjects with active and inactive SLE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAulestia et al., 2016\u003c/p\u003e \u003cp\u003eColombia\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;50 (female; mean 37 \u0026plusmn; 14 y, range 16\u0026ndash;65 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: hormone replacement therapy, prolactinoma, hysterectomy/oophorectomy, pregnancy, lactation, other rheumatic diseases, chronic renal disease, hypothyroidism, drugs interfering with serum PRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL, median): 7.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;6)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/m; mean and IQR)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;6: 7.06, 5.1\u0026ndash;10.2\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;6: 9.7, 5-11.25\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG\u0026oacute;mez-Hern\u0026aacute;ndez et al., 2016\u003c/p\u003e \u003cp\u003eVenezuela\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;50 (female; mean 31 \u0026plusmn; 10.9 y in patients with active disease and 36 \u0026plusmn; 10.4 in patients with inactive disease)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, prolactinoma, drugs interfering with serum PRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;25 ng/mL): 4/50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;3)\u003c/p\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;25 ng/mL) according to SLEDAI\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;3: 0/22\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3: 4/28\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.044\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL; mean and IQR)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;3: 14.2 \u0026plusmn; 7.2\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3: 39.0 \u0026plusmn; 59.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToffoli-Ribeiro et al., 2016\u003c/p\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;62 (female; mean 35.4 \u0026plusmn; 12.2 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;29 (female; mean 32.0 \u0026plusmn; 5.1 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, prolactinoma, drugs interfering with serum PRL, chronic renal failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;25 ng/mL)\u003c/p\u003e \u003cp\u003eSLE: 14/73\u003c/p\u003e \u003cp\u003eControls: 0/29\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL, mean):\u003c/p\u003e \u003cp\u003eSLE: 12.0\u003c/p\u003e \u003cp\u003eControls: 8.8\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL; median and IQR)\u003c/p\u003e \u003cp\u003e0: 8.4, 4.9\u0026ndash;13.9\u003c/p\u003e \u003cp\u003e1\u0026ndash;5: 7.9, 6.1\u0026ndash;14.2\u003c/p\u003e \u003cp\u003e6\u0026ndash;10: 7.7, 5.5\u0026ndash;17.4\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10: 17.1, 10.6\u0026ndash;28.4\u003c/p\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;25 ng/mL) according to SLEDAI\u003c/p\u003e \u003cp\u003e0: 5/46\u003c/p\u003e \u003cp\u003e1\u0026ndash;5: 4/31\u003c/p\u003e \u003cp\u003e6\u0026ndash;10: 3/27\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;10: 10/31\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003eTotal PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.47\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.0001\u003c/p\u003e \u003cp\u003eFree PRL\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.51\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYang et al., 2016\u003c/p\u003e \u003cp\u003eChina\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30 (1 male, 29 female; mean 37.7 \u0026plusmn; 14.1 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;50 (1 male, 24 female; mean 38.4 \u0026plusmn; 9.2 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: NR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eECLIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (mIU/L, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 580 \u0026plusmn; 419.9\u003c/p\u003e \u003cp\u003eControls: 346.0 \u0026plusmn; 227.6\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;5)\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (mIU/L; mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5: 706.1 \u0026plusmn; 485.5\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5: 393.2 \u0026plusmn; 191.3\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.481\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIqbal et al., 2017\u003c/p\u003e \u003cp\u003ePakistan\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;35 (female; mean 23.48 \u0026plusmn; 0.63 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;35 (female; mean 31.25 \u0026plusmn; 0.88 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: steroid therapy, hormone replacement therapy or contraceptive pills, diabetes, liver diseases, hormonal disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 65.45 \u0026plusmn; 4.08\u003c/p\u003e \u003cp\u003eControls: 9.06 \u0026plusmn; 0.59\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eDUSOI\u003c/p\u003e \u003cp\u003eCorrelation PRL and DUSOI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.729\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdelaziz et al., 2018\u003c/p\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;60 (female; mean 33.5 \u0026plusmn; 13.12 y, range 17\u0026ndash;58 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: renal and/or hepatic failure, pregnancy, lactation, hypothyroidism, drugs interfering with serum PRL levels, sex hormones (oral contraceptives, hormone replacement therapy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eImmunoassay (VIDAS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;25 ng/mL: 15/60\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SD): 19.55 \u0026plusmn; 12.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;5)\u003c/p\u003e \u003cp\u003eHyperprolactinemia according to SLEDAI (%)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;5: 3/14\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5: 12/46\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.177\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.323\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWan-Asyraf et al., 2018\u003c/p\u003e \u003cp\u003eMalaysia\u003c/p\u003e \u003cp\u003eCross-sectional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;43 (1 male, 42 female; median: 33 y, IQR 30\u0026ndash;36 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pituitary adenoma, hypothyroidism, drugs interfering with serum PRL levels, sex hormones, chronic renal disease, increased serum levels of liver enzymes and bilirubin, pregnancy, lactation, infection, menopause\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChemiflex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperprolactinemia (\u0026gt;\u0026thinsp;16 ng/mL for male and 20 ng/mL for female): 12/43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI (\u0026gt;\u0026thinsp;4)\u003c/p\u003e \u003cp\u003eHyperprolactinemia according to SLEDAI\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 6/31\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 6/12\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.044\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL, median and IQR)\u003c/p\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;4: 14.34, 11.09\u0026ndash;18.70\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;4: 19.91, 15.95\u0026ndash;22.65\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.014\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e = 0.449\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRaeisi et al., 2018\u003c/p\u003e \u003cp\u003eIran\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40 (female; mean 27.3 \u0026plusmn; 4.12 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;41 (female; mean 28.4 \u0026plusmn; 6.65 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: PCOS, pregnancy, lactation, menopause, abnormal serum levels of liver enzymes, abnormal thyroid function, other autoimmune diseases, drugs interfering with serum PRL levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIEA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 67.82 \u0026plusmn; 7.4\u003c/p\u003e \u003cp\u003eControls: 41.26 \u0026plusmn; 5.8\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eSerum PRL (ng/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eMild activity (SLEDAI 4\u0026ndash;10): 62.55 \u0026plusmn; 4.4\u003c/p\u003e \u003cp\u003eModerate activity (SLEDAI 11\u0026ndash;19): 74.25 \u0026plusmn; 4.6\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were higher in subjects with SLE and moderate disease activity compared to those with mild disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSoliman et al., 2018\u003c/p\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;45 (3 male, 42 female; mean 31 \u0026plusmn; 7.7 y, range 18\u0026ndash;53 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;45 (20 male, 25 female; mean 29.3 \u0026plusmn; 10.5 y, range 16\u0026ndash;58 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: pregnancy, lactation, prolactinoma, drugs interfering with serum PRL, chronic renal failure, hepatic failure, endocrinopathies, psychiatric disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eECLIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum prolactin (ng/mL, mean \u0026plusmn; SD and range)\u003c/p\u003e \u003cp\u003eSLE: 13 \u0026plusmn; 5.3, 6\u0026ndash;27\u003c/p\u003e \u003cp\u003eControls: 11.8 \u0026plusmn; 4.2, 5\u0026ndash;20\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL, mean \u0026plusmn; SD and range)\u003c/p\u003e \u003cp\u003e1\u0026ndash;5: 15.7 \u0026plusmn; 3, 6\u0026ndash;23\u003c/p\u003e \u003cp\u003e6\u0026ndash;10: 16 \u0026plusmn; 4, 8\u0026ndash;27\u003c/p\u003e \u003cp\u003e11\u0026ndash;19: 21.8 \u0026plusmn; 5, 10\u0026ndash;28\u003c/p\u003e \u003cp\u003e20: -\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.007\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI (type of correlation coefficient NR)\u003c/p\u003e \u003cp\u003er\u0026thinsp;=\u0026thinsp;0.022\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.907\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were not higher in subjects with SLE compared to healthy controls, were not overall correlated with disease activity, but increased with increasing SLEDAI score\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSoliman et al., 2023\u003c/p\u003e \u003cp\u003eEgypt\u003c/p\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSLE\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40 (6 male, 34 female; mean 11.5 \u0026plusmn; 2.1 y)\u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;40 (7 male, 33 female; mean 10.7 \u0026plusmn; 1.9 y)\u003c/p\u003e \u003cp\u003eExclusion criteria: hypothyroidism, prolactinoma, renal failure, drugs interfering with serum PRL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum prolactin (ng/mL, mean \u0026plusmn; SD)\u003c/p\u003e \u003cp\u003eSLE: 17.3 \u0026plusmn; 6.6\u003c/p\u003e \u003cp\u003eControls 13.5 \u0026plusmn; 5.3\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003cp\u003eSerum PRL according to SLEDAI (ng/mL, mean \u0026plusmn; SD and range)\u003c/p\u003e \u003cp\u003e4\u0026ndash;8: 14.0 \u0026plusmn; 6.2\u003c/p\u003e \u003cp\u003e8\u0026ndash;12: 17.0 \u0026plusmn; 5.3\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;12 : 19.3 \u0026plusmn; 7.7\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.212\u003c/p\u003e \u003cp\u003eCorrelation PRL and SLEDAI\u003c/p\u003e \u003cp\u003er\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e = 0.368\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerum PRL levels were higher in subjects with SLE compared to healthy controls and were correlated with disease activity\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eNR: not reported\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eBA: biological assay; Chemiflex: chemiluminescent microparticle immunoassay technology with flexible assay protocols; CL: chemoluminescence; DUSOI: Duke Severity of Illness Checklist; ECLAM: European Consensus Lupus Activity Measurement Index; ECLIA: electrochemiluminescence immunoassay; EIA: immunoenzymatic assay; ETA: Enzymun-test assay; FIA: fluorescence immunoassay; IEA: immunoenzymometric assay; IFMA: immunofluorometric assay; IQR: interquartile range; IRMA: immunoradiometric assay; MEIA: Microparticle Enzyme Immunoassay; PRL: prolactin; RIA: radioimmunoassay; r\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e: Pearson\u0026rsquo;s correlation coefficient; r\u003csub\u003e\u003cem\u003es\u003c/em\u003e\u003c/sub\u003e: Spearman\u0026rsquo;s correlation coefficient; SEM: standard error of mean; SLAM: Systemic Lupus Activity Measure; SLE: Systemic Lupus Erythematosus; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCharacteristics of studies examining the effect of dopaminergic agonists on circulating prolactin concentration in systemic lupus erythematosus\u003c/p\u003e \u003cp\u003eThe characteristics of the included studies are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The studies were conducted in the United States\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e, Mexico\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e, Poland\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e,\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e, and China\u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e. Three studies were prospective open-label trials\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e,\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e, and two were randomized clinical trials\u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e,\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e. Two studies with the prospective open-label design included healthy controls to compare the serum levels of inflammatory markers\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. Sample sizes ranged from 7 to 38 subjects with SLE. Three studies assessed the effect of bromocriptine on SLE activity\u003csup\u003e\u003cspan additionalcitationids=\"CR69\" citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e, whereas two studies investigated the impact of quinagolide\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e. Notably, none of the studies included subjects with rapidly progressive or life-threatening SLE.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies (n\u0026thinsp;=\u0026thinsp;5).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor, year, country\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design, aim\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample size, gender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTreatment regimen, follow-up time\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMethod for serum PRL assessment, PRC serum levels\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMethod for disease activity assessment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eResults\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eConclusion\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMcMurray et al., 1995\u003c/p\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProspective open-label trial\u003c/p\u003e \u003cp\u003eTo investigate the efficacy of BRC in suppressing SLE activity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;7 (5 female, 3 male); 26\u0026ndash;48 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBRC: 1.25 mg/d, 1 wk; 2.5 mg/d and monthly 1.25 to 2.5 mg/d increments until serum PRL\u0026thinsp;\u0026lt;\u0026thinsp;3 ng/mL (3.75\u0026ndash;7.5 mg/d)\u003c/p\u003e \u003cp\u003e6\u0026ndash;9 mo during treatment; 5 mo after treatment withdrawal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNR\u003c/p\u003e \u003cp\u003eBefore: 11.2 \u0026plusmn; 1.9 ng/mL\u003c/p\u003e \u003cp\u003e6 mo: 3.1 \u0026plusmn; 1.7 ng/mL\u003c/p\u003e \u003cp\u003eAfter BRC withdrawal: 22.1 \u0026plusmn; 4 ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSLEDAI and SLAM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eSLEDAI score before and after treatment\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBefore: 16.0 \u0026plusmn; 2.0\u003c/p\u003e \u003cp\u003eAt 6 mo: 5.9 \u0026plusmn; 0.8\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.02\u003c/p\u003e \u003cp\u003e\u003cb\u003eSLAM score before and after treatment\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBefore: 11.3 \u0026plusmn; 0.9\u003c/p\u003e \u003cp\u003eAt 6 mo: 6.0 \u0026plusmn; 1.6\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.03\u003c/p\u003e \u003cp\u003e2 mo after BRC withdrawal: 10.4 \u0026plusmn; 1.8\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.02 (vs at 6 mo)\u003c/p\u003e \u003cp\u003e4 mo after BRC withdrawal: 11.4 \u0026plusmn; 0.8\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.03 (vs at 6 mo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBRC treatment reduced SLEDAI score at the 6th month of follow-up\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlvarez et al., 1998\u003c/p\u003e \u003cp\u003eMexico\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized clinical trial\u003c/p\u003e \u003cp\u003eTo investigate the efficacy and safety of BRC as an adjunct to conventional SLE treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBRC: n\u0026thinsp;=\u0026thinsp;36 (35 female, 1 male); 31.5 \u0026plusmn; 9.4 y\u003c/p\u003e \u003cp\u003eControl: n\u0026thinsp;=\u0026thinsp;30 (28 female, 1 male); 32.2 \u0026plusmn; 13.2 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBRC, 2.5 mg/d\u003c/p\u003e \u003cp\u003eBRC: 2\u0026ndash;17 mo (13.1 \u0026plusmn; 3.8 mo)\u003c/p\u003e \u003cp\u003eControl: 1\u0026ndash;17 mo (11.9 \u0026plusmn; 5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eELISA\u003c/p\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003cp\u003eBRC: 24.8 \u0026plusmn; 18.4 ng/mL\u003c/p\u003e \u003cp\u003eControl: 23.7 \u0026plusmn; 22.1 ng/mL\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.42\u003c/p\u003e \u003cp\u003e12 mo\u003c/p\u003e \u003cp\u003eBRC: 5.8 \u0026plusmn; 9 ng/mL\u003c/p\u003e \u003cp\u003eControl: 20.3 \u0026plusmn;14.0 ng/mL\u003c/p\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eSLEDAI score during follow-up\u003c/b\u003e\u003c/p\u003e \u003cp\u003eMo 1\u0026ndash;4; 6\u0026ndash;12\u003c/p\u003e \u003cp\u003eBRC vs control: ns\u003c/p\u003e \u003cp\u003eMo 5:\u003c/p\u003e \u003cp\u003eBRC: 0.9 \u0026plusmn; 1.4\u003c/p\u003e \u003cp\u003eControl: 2.0 \u0026plusmn; 4.5\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003e\u003cb\u003eNo of flares\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBRC: 16 (50%)\u003c/p\u003e \u003cp\u003eControl: 11 (42%)\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.74\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean flares/patient/mo\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBRC: 0.08 \u0026plusmn; 0.11\u003c/p\u003e \u003cp\u003eControl: 0.18 \u0026plusmn; 0.27\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBRC treatment reduced SLEDAI score at the 5th month of follow-up and mean number of flares/patient/month\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHrycek et al. 2001\u003c/p\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProspective open-label trial\u003c/p\u003e \u003cp\u003eTo determine the effect of QNL on serum levels of cytokines in subjects with SLE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSLE: 20 (15 female, 5 male); 31\u0026ndash;44 y\u003c/p\u003e \u003cp\u003eControl: 17 (13 female, 4 male); 30\u0026ndash;43 y (for comparison of cytokine serum levels)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQNL: 12.5 mcg/d, 1 mo; 25 mcg/d, 1 mo; 50 mcg/d, 4 mo\u003c/p\u003e \u003cp\u003e6 mo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003cp\u003eSLE: 355.41 \u0026plusmn;235.37 mIU/L\u003c/p\u003e \u003cp\u003eControl: 230.53 \u0026plusmn; 159.25 mIU/L\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003e3 mo\u003c/p\u003e \u003cp\u003eSLE: 281.95 \u0026plusmn; 181.07 mIU/L\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026gt;\u0026thinsp;0.05 (vs baseline)\u003c/p\u003e \u003cp\u003e6 mo: 195.51 \u0026plusmn; 109.14 mIU/L\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (vs baseline)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eSLEDAI score before and after treatment\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBefore: 13.2 \u0026plusmn; 2.6\u003c/p\u003e \u003cp\u003eAfter: 5.0 \u0026plusmn; 3.0\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eQNL treatment for 6 mo reduced SLEDAI score\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHrycek et al. 2007\u003c/p\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProspective open-label trial\u003c/p\u003e \u003cp\u003eTo determine the effect of QNL on SLEDAI score, acute phase proteins, and IL-6 in subjects with SLE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSLE: 25 (21 female, 4 male); 43.37 \u0026plusmn; 11.85 y\u003c/p\u003e \u003cp\u003eControl: 25 (21 female, 4 male); 52.20 \u0026plusmn; 16.18 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQNL: 12.5 mcg/d, 1 mo; 25\u0026ndash;50 mcg/d, 3 mo\u003c/p\u003e \u003cp\u003e3 mo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIRMA\u003c/p\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003cp\u003eSLE: 16.2 \u0026plusmn; 10.6 ng/mL\u003c/p\u003e \u003cp\u003eControl: 8.55 \u0026plusmn; 4.97 ng/mL\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003cp\u003e3 mo\u003c/p\u003e \u003cp\u003eSLE: 9.33 \u0026plusmn; 4.93 ng/mL\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (vs baseline)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eSLEDAI score before and after treatment\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBefore: 13.4 \u0026plusmn; 2.4\u003c/p\u003e \u003cp\u003eAfter: 7.56 \u0026plusmn; 3.61\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eQNL treatment for 3 mo reduced SLEDAI score\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQian et al., 2015\u003c/p\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized clinical trial\u003c/p\u003e \u003cp\u003eTo investigate the efficacy and safety of BRC as an adjunct to conventional SLE treatment in the postpartum period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBRC: 38 (female); 30.47 \u0026plusmn; 4.33 y\u003c/p\u003e \u003cp\u003eControl: 38 (female); 30.02 \u0026plusmn; 3.95 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBRC, 2.5 mg bid, 14 d (12h after delivery)\u003c/p\u003e \u003cp\u003e12 mo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRIA\u003c/p\u003e \u003cp\u003e2 wk after delivery\u003c/p\u003e \u003cp\u003eBRC: 8.6 \u0026plusmn; 5.0 ng/mL\u003c/p\u003e \u003cp\u003eControl: 72.6 \u0026plusmn; 32.6 ng/mL\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e2 mo after delivery\u003c/p\u003e \u003cp\u003eBRC: 11.5 \u0026plusmn; 7.1 ng/mL\u003c/p\u003e \u003cp\u003eControl: 25.7 \u0026plusmn; 37.6 ng/mL\u003c/p\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSLEDAI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003eSLEDAI score\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBRC: 7.13 \u0026plusmn; 1.37\u003c/p\u003e \u003cp\u003eControl: 6.92 \u0026plusmn; 1.98\u003c/p\u003e \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.43\u003c/p\u003e \u003cp\u003e\u003cb\u003e6 mo\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBRC: 4.25 \u0026plusmn; 1.28\u003c/p\u003e \u003cp\u003eControl: 5.85 \u0026plusmn; 1.76\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u003cb\u003e12 mo\u003c/b\u003e\u003c/p\u003e \u003cp\u003eBRC: 3.42 \u0026plusmn; 0.95\u003c/p\u003e \u003cp\u003eControl: 4.53 \u0026plusmn; 1.15\u003c/p\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBRC treatment for two wk following delivery reduced SLEDAI score at 6 and 12 mo\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eBRC: bromocriptine, ELISA: enzyme-linked immunosorbent assay, IRMA: immunoradiometric assay, NR: not reported, QNL: quinagolide, RIA: radioimmunoassay, SLAM: SLE Activity Measure; SLE: systemic lupus erythematosus, SLEDAI: Systemic Lupus Erythematosus Disease Activity Index.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHyperprolactinemia in systemic lupus erythematosus versus healthy controls\u003c/p\u003e \u003cp\u003eThirteen case-control studies \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan additionalcitationids=\"CR50\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e,\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e,\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e compared the frequency of hyperprolactinemia between subjects with SLE and healthy controls, involving 952 participants. The mean frequency of hyperprolactinemia among subjects with SLE was 30.1%, ranging from 7.1\u0026ndash;87.5%. Pooling data from individual studies revealed that subjects with SLE had a significantly increased odds of hyperprolactinemia (OR 11.69, 95%CI 5.64\u0026ndash;24.22, p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe frequency of hyperprolactinemia was described in nine cross-sectional studies\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e, with a mean of 17%, ranging from 2.19 to 33.3%.\u003c/p\u003e \u003cp\u003eFunnel plot analysis indicated evidence of small studies effect on the association between hyperprolactinemia and SLE (Appendix I).\u003c/p\u003e \u003cp\u003eCirculating prolactin levels in systemic lupus erythematosus versus healthy controls\u003c/p\u003e \u003cp\u003eTwenty-eight studies compared circulating PRL levels between subjects with SLE and healthy controls, comprising 1,860 individuals\u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan additionalcitationids=\"CR34 CR35\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan additionalcitationids=\"CR48 CR49 CR50 CR51\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e,\u003cspan additionalcitationids=\"CR55 CR56 CR57\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e,\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e,\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. Data from 23 studies, including 1,411 subjects \u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan additionalcitationids=\"CR34 CR35\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan additionalcitationids=\"CR49\" citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e,\u003cspan additionalcitationids=\"CR55 CR56 CR57\" citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e,\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e were pooled and revealed that PRL levels were significantly higher among subjects with SLE than in healthy controls (SMD 1.96, 95%CI 1.27\u0026ndash;2.65, p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;95%, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Data from three studies could not be included in the meta-analysis due to lack of description of error values for serum PRL levels\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. One study was excluded from the meta-analysis because overall PRL levels in subjects with SLE were not presented but only according to disease activity status\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, and one study was excluded from the meta-analysis because PRL was assessed by an assay with serum levels not comparable to the other studies\u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e. Notably, the five excluded studies reported significantly higher circulating PRL levels in individuals with SLE than healthy controls.\u003c/p\u003e \u003cp\u003eFunnel plot analysis indicated evidence of small studies effect on the difference between circulating PRL levels between subjects with SLE and healthy controls (Appendix I).\u003c/p\u003e \u003cp\u003eHyperprolactinemia and systemic lupus erythematosus activity\u003c/p\u003e \u003cp\u003eSeven studies examined the association between hyperprolactinemia and SLE activity assessed by the SLEDAI\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e, and data from six \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e were pooled in the meta-analysis. Hyperprolactinemia was associated with increased SLEDAI scores (OR 3.02, 95% CI 1.52-6.00, p 0.002, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Four studies found that hyperprolactinemia was significantly associated with a SLEDAI score greater than 4\u003csup\u003e15,31,41,50\u003c/sup\u003e, which was used as the cutoff value to define disease activity. Only one study used SLEDAI greater than 3 \u003csup\u003e45\u003c/sup\u003e or greater than 5\u003csup\u003e63\u003c/sup\u003e. The first found that hyperprolactinemia was marginally associated with disease activity, whereas the latter found no association.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOne study was not excluded in the meta-analysis because the frequency of hyperprolactinemia was described for various ranges of SLEDAI scores \u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e but described that hyperprolactinemia was significantly associated with disease activity. Funnel plot analysis indicated evidence of small studies effect on the association between hyperprolactinemia and SLE activity (Appendix J).\u003c/p\u003e \u003cp\u003eCorrelation between circulating prolactin levels and systemic lupus erythematosus activity\u003c/p\u003e \u003cp\u003eA total of 26 studies comprising 1,563 subjects addressed the correlation between circulating PRL levels and disease activity\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan additionalcitationids=\"CR52\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e,\u003cspan additionalcitationids=\"CR58 CR59 CR60\" citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e,\u003cspan additionalcitationids=\"CR64 CR65 CR66\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. Nineteen studies employing the SLEDAI to assess disease activity and involving 1,153 individuals could be pooled in the meta-analysis\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e,\u003cspan additionalcitationids=\"CR52\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e,\u003cspan additionalcitationids=\"CR66\" citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. Circulating PRL was positively associated with the SLEDAI score (correlation coefficient: 0.38; 95%CI 0.26\u0026ndash;0.48, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;79.5%, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). When data from studies including other score systems to assess SLE activity were pooled, we found that circulating PRL was positively associated with disease activity (correlation coefficient: 0.34; 95%CI 0.21\u0026ndash;0.45, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;81.5%, 24 studies, 1,313 individuals, Appendix K). Among studies included in the latter meta-analysis, two used the ECLAM score to assess disease activity\u003csup\u003e\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e,\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e, one used the SLAM score\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, and one study used the DUSOI score\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTwo studies were excluded from the meta-analysis because they did not report the correlation coefficient value\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFunnel plot analysis indicated evidence of small studies effect on the correlation between circulating PRL levels and SLE activity (Appendix J).\u003c/p\u003e \u003cp\u003eThe effect of dopaminergic agonists on systemic lupus erythematosus activity\u003c/p\u003e \u003cp\u003eOne prospective open-label trial \u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e and two randomized clinical trials \u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e,\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e assessed the effect of adjunct bromocriptine treatment on measures of SLE activity. All three studies reported that adding bromocriptine to SLE therapy reduced disease activity. McMurray et al. (1995) assessed seven subjects and reported that bromocriptine at maintenance doses ranging from 3.75 to 7.5 mg for six months significantly reduced SLEDAI and SLAM scores\u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e. Alvarez-Nemegyei et al. (1998) conducted a randomized clinical trial in which participants were assigned to receive bromocriptine (2.5 mg/d) or placebo and assessed monthly for up to 12 months. SLEDAI score was significantly lower in the treated group compared to placebo at the fifth month, but not at other time points. Additionally, bromocriptine treatment significantly decreased the mean flare/patient/month\u003csup\u003e69\u003c/sup\u003e. More recently, Qian et al. (2015) reported that bromocriptine treatment at 5 mg/d for 14 days, beginning 12 hours after delivery, significantly reduced SLEDAI score at 6 and 12 months compared to placebo\u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTwo prospective open-label trials investigated whether adjuvant quinagolide treatment affected SLE activity. Hrycek et al. (2001) reported that quinagolide treatment (50 mcg/d, maintenance dose) for six months significantly decreased SLEDAI score compared to baseline in 20 subjects\u003csup\u003e\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Similarly, Hrycek et al. (2007) found that quinagolide at 50 mcg/d (maintenance dose) for three months significantly reduced SLEDAI score compared to baseline in 25 subjects\u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDue to their heterogeneous design, we could not pool the data from the included studies in a meta-analysis.\u003c/p\u003e \u003cp\u003eRisk of bias across studies\u003c/p\u003e \u003cp\u003eAll 15 cross-sectional studies addressing the association between circulating prolactin levels and SLE were considered to have a low risk of bias (Appendix D), whereas two case-control studies were considered to have a high risk of bias and 27 to have a low risk of bias (Appendix E).\u003c/p\u003e \u003cp\u003eAll three open-label trials investigating the effect of dopaminergic agonists on SLE activity were considered to have a low risk of bias (Appendix F), whereas one randomized clinical trial was considered to have a low risk of bias, and the other randomized clinical trial was considered to have a moderate risk of bias (Appendix G).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this systematic review and meta-analysis, we examined whether circulating PRL concentration was different in subjects with SLE compared with healthy controls and whether it was associated with disease activity in SLE. We found that hyperprolactinemia rate and serum PRL levels were significantly higher among individuals with SLE than controls and that serum PRL was moderately correlated with disease activity. In addition, we found that adjunct treatment of SLE with bromocriptine or quinagolide significantly decreased disease activity assessed by the SLEDAI score.\u003c/p\u003e \u003cp\u003eThe association between circulating PRL levels and SLE was addressed in a previous meta-analysis of 25 studies comprising 1,056 subjects with SLE and 426 healthy controls, which reported that circulating PRL levels were significantly higher in SLE than controls and were significantly associated with disease activity\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Our study contributed with updated data from studies published over the last seven years and by additionally examining the effect of PRL suppression on SLE activity. We conducted a detailed literature search and captured 13 additional studies published until 2016 and six studies published since then. In addition to examining circulating PRL levels in SLE and its association with disease activity, we examined the rate of hyperprolactinemia in subjects in SLE. Hence, our study contributed with updated data from studies published over the last seven years and reinforced the previous findings. Moreover, we additionally examined the effect of dopamine agonists on SLE activity. To our knowledge, this is the first systematic review addressing this question.\u003c/p\u003e \u003cp\u003eThe association between circulating PRL and SLE activity in concert with the findings that PRL suppression with dopaminergic agonists decreases disease activity could imply that the association between serum PRL levels and SLE activity is causal. This is further reinforced by the evidence from preclinical studies supporting that the role of PRL in modulating SLE activity is biologically plausible. PRL affects different aspects of innate and acquired immunity. PRL stimulates the inflammatory and phagocytic activity of macrophages \u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e and enhances antigen presentation by activating dendritic cells and inducing the expression of both class II histocompatibility molecules and costimulatory molecules such as CD40, CD80, and CD86\u003csup\u003e9,71\u003c/sup\u003e. Regarding acquired immunity, PRL induces CD4 and CD8 lymphocyte activation by promoting interleukin 2 secretion and inducing the expression of receptors for the latter cytokine, decreasing autoreactive B lymphocyte apoptosis, reducing the threshold for B lymphocyte activation, and increasing immunoglobulin production\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e,\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eStudies involving experimental models of SLE also suggest that hyperprolactinemia may lead to immune dysfunction. In NZB/WF1 mice, which spontaneously develop SLE, hyperprolactinemia induced by pituitary transplants enhances immune dysfunction, organ damage, and increased mortality in both females \u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u003c/sup\u003e and males\u003csup\u003e\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e. PRL administration to R4A-γ2B Balb/c mice induced a lupus-like phenotype, which was reversible following PRL discontinuation\u003csup\u003e\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u003c/sup\u003e. However, the same effect of PRL was not observed in R4A-γ2B C57BL/6 mice, suggesting that the effects of PRL on immune function depend upon the genetic background\u003csup\u003e\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e\u003c/sup\u003e. These findings reinforce the complex pathogenesis of SLE, and it is still unclear how PRL interacts with other factors to affect SLE development and phenotype.\u003c/p\u003e \u003cp\u003eThe role of PRL in modulating immune function has attracted attention to its possible role in affecting autoimmune disease development and severity in humans\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. SLE is considered the prototype systemic autoimmune disease, and there is increasing evidence that PRL may impact immune dysfunction and the clinical phenotype in SLE\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Our meta-analysis reinforces that circulating PRL levels are higher in subjects with SLE than healthy controls and that higher PRL levels are associated with disease activity scores. In light of these findings, we sought to investigate whether decreasing serum PRL would affect SLE activity by conducting a systematic review. Despite the scarcity of studies addressing this question, all five studies included in the review demonstrated that suppressing PRL secretion benefits subjects with SLE.\u003c/p\u003e \u003cp\u003eThe beneficial impact of PRL suppression with dopaminergic agonists supports the role of PRL in determining SLE activity. However, the latter also points to the potential benefit of dopaminergic signaling itself. Indeed, it was previously shown that bromocriptine can affect the immune system independently from hyperprolactinemia. In cell-based studies, dopaminergic signaling induced by agonists reduced the phagocytic activity of macrophages, decreased B lymphocyte proliferation and differentiation in response to mitogenic stimuli, and inhibited the production of interleukin 1 by T lymphocytes\u003csup\u003e\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e,\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u003c/sup\u003e. In addition, Blank et al. (1990) showed that the addition of bromocriptine to cyclosporine in the treatment of subjects with SLE and uveitis reduced the levels of nuclear autoantibodies compared to cyclosporin, independently from circulating prolactin concentrations\u003csup\u003e\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e\u003c/sup\u003e. However, to our knowledge, no other human studies have addressed whether dopaminergic agonists could affect SLE activity independently from their action to suppress PRL secretion.\u003c/p\u003e \u003cp\u003eIt is also unknown whether dopaminergic agonists would be beneficial as monotherapy in subjects with mild disease or how they would affect disease activity compared to established therapy. All included studies in this systematic review assessed the effect of bromocriptine or quinagolide as adjunctive therapy in subjects with SLE. Interestingly, Walker et al. (1999) presented the preliminary findings from a blind randomized clinical trial involving 24 subjects with active SLE, but not organ-threatening disease assigned to receive bromocriptine to lower serum prolactin levels to less than 1 ng/mL (n\u0026thinsp;=\u0026thinsp;11) or hydroxychloroquine at 6 mg/kg (n\u0026thinsp;=\u0026thinsp;13). After one year of treatment, the mean SLEDAI score decreased from 8.6 \u0026plusmn; 2.6 to 2.5 \u0026plusmn; 1.5 in subjects receiving bromocriptine and from 8.2 \u0026plusmn; 1.7 to 4.6 \u0026plusmn; 1.1 in subjects receiving hydroxychloroquine. Additionally, the proportion of individuals decreasing or stopping prednisone, or starting or increasing prednisone dose was similar in both groups\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Although this study was not published as a full-text article, its findings suggest that bromocriptine is comparable to hydroxychloroquine in mild and non-organ-threatening SLE.\u003c/p\u003e \u003cp\u003eAnother possibility that should be considered is that circulating PRL may be a biomarker of SLE activity instead of having a significant contributory role in disease activity. Indeed, hyperprolactinemia has been reported in different autoimmune diseases, as thoroughly reviewed elsewhere\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e79\u003c/span\u003e\u003c/sup\u003e, and also in non-autoimmune inflammatory disorders, such as insulin resistance \u003csup\u003e\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e,\u003cspan citationid=\"CR81\" class=\"CitationRef\"\u003e81\u003c/span\u003e\u003c/sup\u003e and atherosclerosis\u003csup\u003e\u003cspan citationid=\"CR82\" class=\"CitationRef\"\u003e82\u003c/span\u003e,\u003cspan citationid=\"CR83\" class=\"CitationRef\"\u003e83\u003c/span\u003e\u003c/sup\u003e. However, prospective studies are warranted to validate circulating PRL as a disease biomarker.\u003c/p\u003e \u003cp\u003eIt is noteworthy that eight studies reported that circulating PRL levels were not different between subjects with SLE and healthy controls\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e,\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e,\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e,\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e,\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e, and 13 studies found no correlation between circulating PRL and SLE activity\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e,\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e,\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e,\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. The reasons for the inconsistent findings between studies are not clear. However, they could be due to the different characteristics of the participants and to characteristics of the association between PRL and SLE and its activity that were not addressed in the methodological design of the included studies. It is reasonable to speculate that sustained but not sporadic increases in circulating PRL could determine its association with immune dysfunction, and a single measurement of serum PRL levels, as was the case in all included studies, would lead to inappropriate conclusions.\u003c/p\u003e \u003cp\u003eAnother point that should be considered in interpreting our findings is that posttranslational changes in PRL may influence the association between PRL and SLE. Three forms of PRL are found in the circulation, including monomeric PRL, dimeric PRL, and macro-PRL, being the latter two biologically inactive\u003csup\u003e\u003cspan citationid=\"CR84\" class=\"CitationRef\"\u003e84\u003c/span\u003e\u003c/sup\u003e. Routine PRL assays cannot distinguish between monomeric PRL and macro-PRL\u003csup\u003e\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e\u003c/sup\u003e, and it is, therefore, possible that hyperprolactinemia found in different studies addressing the association between circulating PRL and SLE vary with respect to the concentration of monomeric PRL that contributes to increased PRL levels. Therefore, hyperprolactinemia may not reflect increased levels of biologically active PRL. Indeed, two studies included in this review found that free (monomeric) PRL, but not total PRL levels, were associated with SLE activity\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis systematic review has some limitations that should be considered when interpreting our findings. The studies addressing circulating PRL levels in SLE were overall small and varied in the characteristics of the participants. Many studies included pre and postmenopausal women and men and did not present data according to sex and menopausal status. Therefore, we could not conduct subgroup analysis according to these variables. It is, hence, unknown whether the magnitude of the association between PRL and SLE and its activity varies with age, gender, and menopausal status in women. Moreover, the time since SLE diagnosis varied between subjects in the included studies, but we could not examine its effect on the association between serum PRL and SLE and its activity.\u003c/p\u003e \u003cp\u003eIn addition, the systematic review addressing the effect of dopaminergic agonists in SLE activity was limited by the impossibility of conducting a meta-analysis due to the heterogeneity of the included studies, such as the type of dopaminergic agonist assessed, the type of population, and the study design. Moreover, the studies were overall small, with few individuals included. Notwithstanding, the findings from our review raise questions that should be addressed in future studies, including if dopaminergic agonists would benefit individuals with severe SLE as adjunctive therapy or how they would compare to standard treatment in milder disease. Moreover, whether the effects of dopaminergic agonists solely dependent upon PRL suppression and, if so, what the optimal level of suppression would be is currently unknown. It should also be pointed out that cabergoline, a potent and long-acting dopaminergic agonist\u003csup\u003e\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e\u003c/sup\u003e, was not studied in individuals with SLE. Due to its prolonged half-life, cabergoline has greater efficacy in suppressing PRL secretion, fewer adverse effects, and more convenient dosing compared with bromocriptine and quinagolide, which would increase tolerability and compliance\u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e \u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn conclusion, this systematic review and meta-analysis indicates hyperprolactinemia rates and serum PRL levels are significantly higher among individuals with SLE compared with controls and that serum PRL is moderately correlated with disease activity. Moreover, adjunctive treatment with the dopaminergic agonists bromocriptine and quinagolide is effective in decreasing SLE activity in individuals without rapidly progressive or life-threatening disease.\u003c/p\u003e \u003cp\u003eThe findings from this systematic review also raise several points that should be addressed in future studies to improve our understanding of the link between PRL and SLE, including whether the association between circulating PRL and SLE varies with age, sex, menopausal status, time since SLE diagnosis, persistent versus sporadic serum PRL elevation, or the increase of different circulating forms of PRL. Given the correlation between PRL and SLE activity, it would also be interesting to explore the role of PRL as a biomarker of disease activity by examining the impact of SLE therapy on circulating PRL in prospective studies. Moreover, it would be important to reassess the effect of dopaminergic agonists on SLE activity, given the availability of cabergoline, which has a more favorable tolerability profile.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest:\u003c/h2\u003e \u003cp\u003ethe authors declare no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003ethis work had no funding.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eA.A.C.: Conceptualization, Methodology, Data curation, Writing: original draft preparation.L.F.C.: Conceptualization, Methodology, Data curation, Writing: original draft preparation.C.L.L.: Data curation; Writing: Reviewing and Editing.L.D.C.M.: Conceptualization, Methodology, Data curation, Writing: Reviewing and Editing.L.A.C.R.M: Conceptualization, Methodology, Data curation, Writing: Reviewing and Editing.A.A.A.: Conceptualization, Methodology, Data curation, Writing: Reviewing and Editing.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe are thankful to Cinthia Gabriel Meireles, Licia Maria Henrique da Mota, and Luciana Ansaneli Naves for the intellectual discussions that contributed to the work.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data generated or analyzed during this study are included in the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLisnevskaia, L., Murphy, G. \u0026amp; Isenberg, D. 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Bmj 338, b381 (2009).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"systemic lupus erythematosus, prolactin, disease activity, dopaminergic agonists, bromocriptine, quinagolide","lastPublishedDoi":"10.21203/rs.3.rs-4477148/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4477148/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis systematic review of clinical studies investigated whether circulating PRL levels differed between subjects with systemic lupus erythematosus (SLE) and healthy controls, the correlation between circulating PRL and SLE activity, and the effect of dopaminergic agonists as adjuvant therapy for SLE. We searched PubMed, Scopus, Web of Science, Cochrane, Embase, and Google Scholar for case-control and cross-sectional studies investigating circulating PRL levels in subjects with SLE and/or its correlation with disease activity, and clinical trials examining the effect of dopaminergic agonists on SLE activity assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score. Forty-five studies addressing circulating PRL levels in SLE met our inclusion criteria. SLE was associated with an increased odds of hyperprolactinemia (OR 11.69, 95%CI 5.64\u0026ndash;24.22) and circulating PRL levels were significantly higher in subjects with SLE than in controls (standardized mean difference of 1.96, 95%CI 1.27\u0026ndash;2.65). Circulating PRL was positively correlated with SLE activity assessed by the SLEDAI (correlation coefficient 0.38, 95% CI 0.26\u0026ndash;0.48). Two randomized clinical trials with bromocriptine and three prospective open-label trials with quinagolide reported that treatment with dopaminergic agonists was associated with reduced frequency of disease flare and decreased SLEDAI score. Circulating PRL levels were higher in subjects with SLE than in healthy controls and are significantly associated with disease activity. In addition, treatment with the dopaminergic agonists bromocriptine and quinagolide reduced SLE disease activity and may be a beneficial adjuvant therapy for the disease. This review was registered in PROSPERO (CRD42021237156).\u003c/p\u003e","manuscriptTitle":"Circulating prolactin levels and the effect of dopaminergic agonists in systemic lupus erythematosus: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-14 18:40:58","doi":"10.21203/rs.3.rs-4477148/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-20T05:57:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-15T01:23:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"77142748459954945006178685895833393374","date":"2024-08-04T23:21:50+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-24T12:51:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"80322235151128616225754198446309745550","date":"2024-06-10T08:59:01+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-07T10:27:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-07T10:26:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-04T13:38:06+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-31T11:48:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-25T14:16:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8b06bfb8-bd95-4f47-b83d-3c6bec396eda","owner":[],"postedDate":"June 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33180806,"name":"Health sciences/Endocrinology"},{"id":33180807,"name":"Health sciences/Rheumatology"}],"tags":[],"updatedAt":"2024-12-09T16:17:19+00:00","versionOfRecord":{"articleIdentity":"rs-4477148","link":"https://doi.org/10.1038/s41598-024-74749-y","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-12-03 15:58:00","publishedOnDateReadable":"December 3rd, 2024"},"versionCreatedAt":"2024-06-14 18:40:58","video":"","vorDoi":"10.1038/s41598-024-74749-y","vorDoiUrl":"https://doi.org/10.1038/s41598-024-74749-y","workflowStages":[]},"version":"v1","identity":"rs-4477148","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4477148","identity":"rs-4477148","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}