Prolactin Response to Metformin in Cabergoline-Resistant Prolactinomas: A Pilot Study.

INTRODUCTION: Cabergoline is the treatment of choice for prolactinomas. However, 10-20% of prolactinomas are resistant to cabergoline. Metformin, a biguanide widely used in the treatment of diabetes mellitus, has been shown to reduce prolactin secretion in various pituitary tumor-cell lineages both in vitro and in vivo and in human pituitary adenomas in vitro. The aim of this study is to test the effects of metformin addition to cabergoline treatment on prolactin levels in patients with resistant prolactinomas. SUBJECTS AND METHODS: This is a prospective study performed in an outpatient clinic in a reference center. Ten adult patients (26-61 years) with prolactinomas (7 M), persistent hyperprolactinemia (38-386 ng/mL) under cabergoline treatment (2-7 mg/week) for at least 6 months (6-108 months), features of metabolic syndrome, and not taking metformin were included. Metformin (1.0-2.5 g v.o./day) was given according to patients' tolerance. Cabergoline doses were kept unchanged. Serum prolactin levels were measured before and after short- (30-60 days) and long-term (120-180 days) metformin treatment. RESULTS: Mean prolactin levels did not show any significant changes (148 ± 39 vs. 138 ± 42 vs. 133 ± 39 ng/mL, before, at 30-60 days, and at 120-180 days, respectively, p = 0.196) after metformin (mean dose: 1.25 g/day; range: 1.0-2.0 g/day). No patient reached a normal prolactin level during metformin treatment. Two patients were considered partial responders for exhibiting prolactin decreases ≥50% at a single time point during metformin. CONCLUSION: Metformin addition to ongoing high-dose cabergoline treatment in patients with cabergoline-resistant prolactinomas failed to show a consistent inhibitory effect in serum prolactin levels.

Prevalence of Hyperprolactinemia and Clinically Apparent Prolactinomas in Men Undergoing Fertility Evaluation.

OBJECTIVE: To determine prevalence of hyperprolactinemia and prolactinoma among men presenting for initial fertility evaluation. METHODS: We performed a retrospective review of men presenting for initial fertility evaluation at a tertiary care, academic health system between 1999 and 2018. Men with measured prolactin levels were analyzed to determine prevalence of hyperprolactinemia and prolactinoma. We compared clinical characteristics of men with and without hyperprolactinemia. Univariable and multivariable analysis were used to determine factors associated with hyperprolactinemia. We assessed effects of hyperprolactinemia and prolactinoma on testosterone levels, semen parameters and pregnancy outcomes after treatment. RESULTS: A total of 3101 men had serum prolactin level measured. 65 (2.1%) had hyperprolactinemia. Patients with hyperprolactinemia had lower testosterone (median 280 ng/dL vs 313 ng/dL, P = 0.038) and lower total motile sperm count (median 7.0 million vs 34.7 million, P = 0.001) compared to men without hyperprolactinemia. 43.1% of men with hyperprolactinemia had oligospermia vs 21.5% of men without hyperprolactinemia (P<0.001). Univariable analysis demonstrated that men with elevated luteinizing hormone (LH) (OR 1.077, P = 0.001) and follicle-stimulating hormone (FSH) (OR 1.032, P = 0.002) were more likely to have hyperprolactinemia. Men with oligospermia were more likely to have hyperprolactinemia (OR 2.334, P = 0.004). On multivariable analysis, neither hormone parameters nor oligospermia were associated with elevated prolactin (P>0.05). Of the 65 men with hyperprolactinemia, 11 (17%) were diagnosed with a prolactinoma, resulting in an overall prevalence of 11 in 3101 (0.35%). CONCLUSION: The overall prevalence of prolactinoma in our cohort of men undergoing fertility evaluation was 35-fold higher than the prevalence in the general male population.

Establishment of reference intervals of monomeric prolactin to identify macroprolactinemia in Chinese patients with increased total prolactin.

BACKGROUND: Macroprolactin is responsible for pseudohyperprolactinemia and is a common pitfall of the prolactin immunoassay. We aimed to determine the frequency of macroprolactinemia in Chinese hyperprolactinemic patients using monomeric prolactin discriminated by precipitation with polyethylene glycol (PEG). METHODS: Post-PEG monomeric prolactin gender-specific reference intervals were established for the Elecsys immunoassay method (Roche Diagnostics) using sera from healthy female (n = 120) and male (n = 120) donors. The reference intervals were validated using 20 macroprolactinemic (as assessed by gel filtration chromatography (GFC)) sera samples, and presence of monomeric prolactin was discriminated by GFC. Patients with high total prolactin were then screened by PEG precipitation to analyze macroprolactin. The demographic and biochemical details of patients with true hyperprolactinemia and macroprolactinemia were compared. RESULTS: Reference intervals for monomeric prolactin in females and males were 3.4-18.5 and 2.7-13.1 ng/mL, respectively. Among 1140 hyperprolactinemic patients, macroprolactinemia was identified in 261 (22.9 %) patients while the other 879 (77.1 %) patients were diagnosed with true hyperprolactinemia. Menstrual disturbances were the most common clinical feature in both groups. Galactorrhea, amenorrhea, and visual disturbances occurred more frequently in true hyperprolactinemic patients (P < 0.05). CONCLUSIONS: The prevalence of macroprolactin in Chinese patients with hyperprolactinemia was described for the first time. Monomeric prolactin concentration, along with a reference interval screening with PEG precipitation, provides a diagnostic approach for hyperprolactinemia with improved accuracy.

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

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

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

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

[Hyperprolactinemia and antipsychotics: it's not always what it seems to be]. / Jongeren met hyperprolactinemie bij antipsychoticagebruik: denk aan macroprolactine.

Hyperprolactinemia is a relatively frequent laboratory abnormality (30-80%) as a result of antipsychotics and a reason to reduce or stop them. We describe two youngsters with autism spectrum disorder whose hyperprolactinemia was based on a false-positive laboratory finding due to macroprolactin. The consequences were: unnecessary endocrinological evaluation including a brain MRI, and undesirable antipsychotic dose reduction. Thus, hyperprolactinemia can be due to a falsely elevated prolactin concentration. There should be an addition to the current guidelines in which a work-up for macroprolactin screening is included.

Altered immunoglobulin G glycosylation in patients with isolated hyperprolactinaemia.

Prolactin is a peptide hormone produced in the anterior pituitary, which increase in several physiological and pathological situations. It is unclear if hyperprolactinaemia may affect glycosylation of immunoglobulin G (IgG). Twenty-five patients with hyperprolactinemia and 22 healthy control subjects were included in the study. The groups had similar age and gender distribution. A panel of hormonal and haematological analyses, creatinine, glucose, liver enzymes and immunoglobulins were measured by routine clinical methods. IgG was purified from serum by Protein G Sepharose. Sialic acid was released from IgG by use of neuraminidase followed by quantification on high performance anion-exchange chromatography with pulsed amperometric detection. Tryptic glycopeptides of IgG was analysed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Hormone and immunoglobulin levels were similar in the two groups, except for IgA and prolactin. Significantly higher IgG1 and IgG2/3 galactosylation was found in the patient group with hyperprolactinaemia compared to controls. (A significant correlation between prolactin and IgG2/3 galactosylation (Rs 0.61, p<0.001) was found for samples with prolactin values below 2000 mIU/L. The relative amount of sialylated and bisecting glycans on IgG did not differ between patients and controls. The four macroprolactinaemic patients showed decreased relative amount of bisecting IgG2/3 glycans. Hyperprolactinaemia was found to be associated with increased galactosylation of IgG1and IgG2/3. This may have impact on IgG interactions with Fc-receptors, complement and lectins, and consequently lead to an altered immune response.

Intracranial Germinoma Misdiagnosed as Hyperthyroidism: A Case Report and Review of the Literature.

Intracranial germ cell tumors (GCTs) are relatively rare, which account for 0.5% of all primary intracranial neoplasms. Intracranial germinomas most commonly occur in the pineal and suprasellar region, making up the majority of all intracranial GCTs. For its diversified clinical manifestations, the diagnosis is easily confused with other diseases. Here, we present a case of a 19-year-old boy with intracranial germinoma who was preliminarily misdiagnosed as hyperthyroidism for the symptoms of weight loss and thyroid dysfunction.

Cardiometabolic Risk Factors in Men with Elevated Macroprolactin Content: A Pilot Study.

BACKGROUND: Macroprolactinemia is a condition associated with the presence of large amounts of high molecular weight complexes of prolactin. Despite high prevalence, clinical significance of macroprolactin remains poorly understood. OBJECTIVE: The aim of this study was to assess cardiometabolic risk in men with isolated macroprolactinemia. METHODS: The study population included 11 men with isolated macroprolactinemia, 14 subjects with monomeric hyperprolactinemia and 14 men with prolactin levels within the reference range. Glucose homeostasis markers, plasma lipids, as well as plasma levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine and 25-hydroxyvitamin D were determined in all included patients. RESULTS: Compared to healthy counterparts, men with isolated macroprolactinemia had higher levels of 2-h postchallenge glucose, hsCRP and fibrinogen, lower levels of 25-hydroxyvitamin D and reduced insulin sensitivity. Patients with monomeric hyperprolactinemia were characterized by increased plasma levels of 2-h postchallenge glucose, triglycerides, uric acid, hsCRP, fibrinogen and homocysteine, reduced insulin sensitivity and decreased plasma concentrations of HDL cholesterol and 25-hydroxyvitamin D. Subjects with isolated macroprolactinemia differed from patients with monomeric hyperprolactinemia in postchallenge plasma glucose, insulin sensitivity, uric acid, hsCRP, fibrinogen, homocysteine and 25-hydroxyvitamin D. In men with monomeric hyperprolactinemia, uric acid, hsCRP, fibrinogen, homocysteine and 25-hydroxyvitamin D, while in men with elevated levels of macroprolactin, uric acid, hsCRP, fibrinogen and 25-hydroxyvitamin D correlated with a content of monomeric prolactin or macroprolactin, respectively, as well as with a degree of insulin sensitivity. CONCLUSIONS: The obtained results suggest that macroprolactinemia may increase cardiometabolic risk but to a lesser extent than monomeric hyperprolactinemia.

The Impact of Ethinyl Estradiol on Metformin Action on Prolactin Levels in Women with Hyperprolactinemia.

BACKGROUND: Metformin reduced prolactin levels only in women with hyperprolactinemia. OBJECTIVE: The purpose of this case-control study was to compare metformin action on lactoctrope function between women receiving oral contraceptive pills and women not using hormonal contraception. METHODS: The study included two groups of matched women with elevated prolactin levels and new-onset prediabetes or diabetes. The first group consisted of 20 women using oral contraceptive pills for at least 12 months before entering the study, while the second group included 20 patients not using any hormonal contraception. Over the whole study period, all women were treated with metformin (1.7-3 g daily). Circulating levels of glucose, insulin, prolactin, thyrotropin, free thyroid hormones, adrenocorticotropic hormone, gonadotropins and insulin-like growth factor-1 were measured at the beginning and at the end of the study (16 weeks later). RESULTS: Thirty-eight patients completed the study. Metformin reduced plasma glucose levels and improved insulin sensitivity but the latter effect was stronger in women receiving oral contraceptive pills than in women not using any contraception. Although metformin treatment decreased plasma prolactin levels in both study groups, this effect was stronger in women taking oral contraceptive pills. Only in this group of women, metformin increased plasma luteinizing hormone levels. The changes in plasma prolactin correlated with their baseline insulin sensitivity and the effect of metformin on insulin sensitivity. Metformin did not affect plasma levels of thyrotropin, free thyroxine, free triiodothyronine, follicle-stimulating hormone, adrenocorticotropic hormone and insulin-like growth factor-1. CONCLUSIONS: The obtained results suggest that the effect of metformin on overactive lactotropes depends on estrogen levels.

Antipsychotics-induced hyperprolactinemia and screening for macroprolactin.

INTRODUCTION: High prolactin (PRL) concentrations are found in laboratory test results of patients on majority of antipsychotic drugs. Prevalence rates and degrees of severity of hyperprolactinemia (HPRL) based on PRL concentration may depend on the presence of macroprolactin in the serum. The aim of the study was to investigate the difference between PRL concentrations before and after precipitation of macroprolactin and to examine if there were any changes in the categorization of HPRL between samples prior and after precipitation. MATERIALS AND METHODS: Total of 98 female patients (median age 33; range 19-47 years) diagnosed with a psychotic disorder, proscribed antipsychotic drugs, and with HPRL were included. Total PRL concentration and PRL concentration after macroprolactin precipitation with polyethylene glycol (postPEG-PRL) were determined by the chemiluminometric method on the Beckman Coulter Access2 analyser. RESULTS: Total PRL concentrations (median 1471; IQC: 1064-2016 mlU/L) and postPEG-PRL concentrations (median 1453; IQC: 979-1955 mlU/L) were significantly correlated using intraclass correlation coefficient for single measurements (mean estimation 0.96; 95%CI 0.93-0.97) and average measurement (mean estimation 0.98; 95%CI 0.96-0.99), and all investigated female patient had HPRL according to PRL and postPEG-PRL concentration. The median PRL recovery following PEG precipitation was 95; IQC: 90-100%. There was substantial agreement (kappa test = 0.859, 95% CI: 0.764-0.953) between the categories of HPRL severity based on total PRL concentrations and postPEG-PRL concentrations. CONCLUSION: The study demonstrated that HPRL was present in all subjects using the reference interval for total PRL concentration and postPEG-PRL concentration with no significant impact of macroprolactin presence in the serum on the categorization of patients according to severity of HPRL.

Correlation between Prolactin and Symptom Profile in Acute Admitted Women with Recurrent Schizophrenia.

BACKGROUND: The prevalence of hyperprolactinemia among psychiatric patients receiving antipsychotic medications was estimated to be between 30% and 70%. A review of the literature on prolactin and schizophrenia symptoms suggests that the correlation between them is complex and not limited to the adverse effects of antipsychotics. Relations with specific symptom dimensions have not been found consistently across studies. The association between increased prolactin and recurrent episodes of schizophrenia needs to be replicated in larger samples and in a population of female patients. The aim of this study was to find out whether elevated prolactin is related to specific symptoms or dimensions of schizophrenia, which is a heterogenic entity. SUBJECTS AND METHODS: The sample consisted of 119 consecutively acute admitted women, aged 18 to 45 years with recurrent schizophrenia diagnosed on bases of DSM-5 criteria. Assessment for all the enrolled subjects comprised a psychiatric evaluation and blood draw to determine the prolactin level. Symptoms of schizophrenia were determined using the Positive and Negative Syndrome Scale (PANSS). Data were analyzed by regression analysis and the Independent Samples t Test. Values are given as means ±SD. RESULTS: Hyperprolactinemia was detected in 74.79% patients (n=89), whereas the group without hyperprolactinemia comprised 25.21% of the sample. When plasma prolactin levels and clinical features between groups were compared, there was a statistically significant difference in the negative subscale scores of the PANSS (p=0.0011), positive subscale scores of the PANNS (p=0.0043), general subscale scores of the PANSS (p=0.0226) and total scores of the PANNS (p=0.0003). CONCLUSION: There were statistically significant differences in the clinical symptoms between two compared groups in total score and in the positive, negative and general subscores.

Effect of Brexpiprazole on Prolactin and Sexual Functioning: An Analysis of Short- and Long-Term Study Data in Major Depressive Disorder.

PURPOSE/BACKGROUND: Evidence supports use of adjunctive atypical antipsychotics in major depressive disorder (MDD). Impaired sexual functioning is common in MDD and may be worsened by antipsychotic adverse effects. We evaluated the effect of brexpiprazole on prolactin and sexual functioning in patients with MDD. METHODS/PROCEDURES: In short-term studies, patients received adjunctive brexpiprazole 1, 2, or 3 mg or placebo. The long-term study was a flexible-dose (0.5-3 mg/d) open-label extension (OLE). Change from baseline and shifts in prolactin status and prolactin-related treatment-emergent adverse events (TEAEs) were assessed. Sexual functioning was assessed by the Massachusetts General Hospital Sexual Functioning Questionnaire. FINDINGS/RESULTS: Median changes in prolactin levels from baseline to week 6 in short-term studies were as follows: brexpiprazole, 5.99 ng/mL (females) and 1.61 ng/mL (males); placebo, -0.15 ng/mL (females) and -0.08 ng/mL (males).Median changes from baseline to week 52 in the OLE were as follows: 0.27 ng/mL (females) and 0.27 ng/mL (males). Prolactin levels in patients with baseline prolactin greater than 1× upper limit of normal values tended to decrease over time.The proportion of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies for both sexes was low (0%-0.3%) and did not differ from placebo: OLE, 0.5% (females) and 0.8% (males).In short-term studies, the incidence of prolactin-related TEAEs was 3.1% for brexpiprazole and 0.7% for placebo (OLE, 3.1%). There were overall numerical improvements from baseline in sexual functioning for females and males after short- and long-term brexpiprazole treatment, with statistically significant improvements for brexpiprazole versus placebo in females on the items 'interest in sex' (-0.19; 95% confidence interval [CI], -0.33 to -0.05; P = 0.0074), 'sexually aroused' (-0.17; 95% CI, -0.30 to -0.03; P = 0.0154), and 'overall sexual satisfaction' (-0.16; 95% CI, -0.30 to -0.03; P = 0.0184). IMPLICATIONS/CONCLUSIONS: There were small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, low incidences of prolactin-related TEAEs, and modest improvements in sexual functioning with adjunctive brexpiprazole in MDD.

Hyperprolactinemia in Acromegaly is Related to Prolactin Secretion by Somatolactotroph Tumours.

The aim of this study is to assess differences in patient characteristics, tumour characteristics and hormone levels between acromegalic patients with and without hyperprolactinemia. 44 patients of the University Hospital of Brussels, Belgium with acromegaly who were diagnosed between January 2007 and July 2018 were included in this study. Nineteen patients were classified in the hyperprolactinemia group and 25 patients were classified in the normoprolactinemia group. No significant differences between acromegalic patients with and without hyperprolactinemia were found in age at diagnosis, gender, presence of hyperprolactinemia symptoms, insulin-like growth factor 1, growth hormone and testosterone levels, tumour volume, tumour invasiveness, immunohistochemistry of growth hormone and prolactin, Ki-67 index and mitotic index. However, for a cut-off of 10% of prolactin-positive cells, there was a trend towards a higher percentage of prolactin-positive tumours in hyperprolactinemia patients (p=0.054) and higher mean prolactin level in case of positive prolactin immunostaining (p=0.007)). In our study there were no differences in characteristics between acromegaly patients with hyper- and normoprolactinemia. An association between the serum prolactin level and the positivity of prolactin immunohistochemistry of the adenoma tissue was found. The absence of a difference in tumour volume between patients with hyper- and normoprolactinemia suggests that the hyperprolactinemia is likely to be caused by the co-secretion of growth hormone and prolactin by the tumour. Finally, for the first time, the cut-off of 10% of prolactin cells was validated for the diagnosis of somatolactotroph tumours in acromegaly.

Ovarian cyclicity and prolactin status of African elephants (Loxodonta africana) in North American zoos may be influenced by life experience and individual temperament.

Hyperprolactinemia is an endocrine disorder associated with infertility in many species, including elephants. In a recent survey of zoos accredited by the Association of Zoos and Aquariums (AZA), over half of African elephant females (N = 101) were not cycling normally, 30% of which exhibited hyperprolactinemia. We examined whether life experience and temperament predict ovarian cyclicity and circulating prolactin status in individual African elephant females. We hypothesized that, similar to humans, acyclicity and hyperprolactinemia in elephants will be associated with an apprehensive or fearful, anxious temperament, and an increased number of potentially challenging life events (transfers, deaths and births). Ninety-five adult African elephant females housed at 37 AZA institutions were included in this study. Blood samples were collected twice a month for 1 year to determine ovarian cycle (cycling, n = 44; irregular, n = 13; non-cycling, n = 38) and prolactin (normal, n = 44; low; n = 23; high; n = 28) status. Keeper ratings on a 6-point scale were obtained on 32 temperament traits in 85 of these elephants. We determined that giving birth and being exposed to herd mates entering the facility were positively associated with normal ovarian cycle and prolactin profiles. By contrast, age, serum cortisol, and an increased number of herd mates leaving a facility were negatively associated with both. Contrary to our hypothesis, hyperprolactinemia was associated with a popular and caring temperament rating, whereas consistently low prolactin was associated with a fearful, apprehensive temperament. These findings indicate that pituitary-ovarian function may be impacted by life history (cyclicity) and temperament (prolactin), which should be taken into consideration when making management decisions.

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

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

Macroprolactinemia Attenuates the Impact of Levothyroxine on Hypothalamic-Pituitary-Thyroid Axis Activity and Thyroid Autoimmunity in Women With Autoimmune Hypothyroidism.

Because of contradictory results, clinical significance of elevated levels of macroprolactin (macroprolactinemia) remains unclear. The aim of this study was to investigate whether macroprolactinemia determines levothyroxine action on hypothalamic-pituitary-thyroid axis activity and thyroid antibody titers in women with autoimmune hypothyroidism. The study population included 2 age-, body mass index-, hormone-, and thyroid antibody-matched groups of premenopausal women with untreated autoimmune subclinical hypothyroidism: 15 subjects with coexisting macroprolactinemia and 29 individuals with prolactin levels within the reference range. All included patients were then treated with levothyroxine for 6 months. Serum levels of thyrotropin, free thyroid hormones, prolactin and 25-hydroxyvitamin D, titers of thyroid peroxidase and thyroglobulin antibodies, as well as macroprolactin content were assessed at the beginning and at the end of the study. Except for 25-hydroxyvitamin D levels and macroprolactin content, there were no significant differences between both study arms in the investigated markers. All participants completed the study. In both treatment arms, levothyroxine treatment decreased thyrotropin levels, increased free thyroxine and free triiodothyronine levels, as well as reduced thyroid peroxidase titers, but this effect was less pronounced in women with macroprolactinemia. In women with normal prolactin levels, levothyroxine reduced also thyroglobulin antibody titers and increased 25-hydroxyvitamin D levels. In this group of patients, treatment-induced changes in hormone levels and thyroid antibody titers correlated with treatment-induced changes in 25-hydroxyvitamin D levels. The obtained results suggest that macroprolactin excess attenuates the impact of levothyroxine on hypothalamic-pituitary-thyroid axis activity and thyroid autoimmunity.

Macroprolactinemia Detection by Magnetically Assisted Polyethylene Glycol Precipitation: Potential for Automation.

BACKGROUND: Macroprolactin is an immunoglobulin-prolactin complex that is not bioactive in vivo but the prolactin component remains immunoreactive. The complex is a universal source of interference in prolactin immunoassays and commonly results in misdiagnosis of hyperprolactinemia with consequent clinical mismanagement of patients. Removal of macroprolactin by precipitation with polyethylene glycol (PEG) is an effective technique for identifying such patients but unfortunately not universally employed due to the manual nature of the procedure. METHODS: We developed a modified PEG precipitation technique using magnetic nanoparticles that we termed Magnetically Assisted PEG Precipitation (MAPP). This procedure was verified against an established PEG precipitation procedure. RESULTS: The MAPP procedure we developed was robust, reproducible, and affords the potential for automation of macroprolactin screening in clinical laboratories. Comparisons of prolactin levels obtained following MAPP in sera from patients with either true hyperprolactinemia or macroprolactinemia generated results comparable to that of conventional PEG precipitation. CONCLUSIONS: The MAPP technique yields results comparable to those of traditional PEG precipitation. Elimination of the need for centrifugation affords the possibility of automation and hence more widespread adoption of routine PEG screening by clinical laboratories.

Immunomodulating Effects Depend on Prolactin Levels in Patients with Hyperprolactinemia.

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