Big Prolactin Research Articles

Prolactin Monomeric Polyethylene Glycol Measurement Method and Study of Reference Value Verification

Purpose: Prolactin in the blood is separated into three types, and over 90% of prolactin presents as a double monomer (23 KDa). Rarely, it can exist in the size of big prolactin (150 KDa), which is called macroprolactin and is known as an autoantibody complex. When macroprolactin accounts for more than 60% of prolactin in the blood, it is called macroprolactinemia. The presence of such macroprolactin was first reported in a patient with hyperprolactinemia but without typical symptoms. Macroprolactinemia is emerging as an important cause of idiopathic hyperprolactinemia. The polyethylene glycol (PEG) precipitation method using the property of precipitating large-molecular-weight proteins is simple and recently has been widely used as a screening test. The results are in good agreement with the results of gel chromatography. The purpose of this study was to confirm the measurement method and reference value verification of monomeric prolactin in blood prolactin using the PEG precipitation method. Materials and Methods: For 40 examinees who visited the Gangnam Center of Seoul National University Hospital in 2021, the prolactin level was verified using radioimmunoassay (RIA). For macroprolactinemia PEG precipitation method, 25% PEG (molecular weight 6000kDa) solution and serum were mixed in equal amounts in a test tube, then left at room temperature for 20 minutes and centrifuged at 4℃ for 30 minutes (1500g). The prolactin level was measured in the supernatant. Results : After confirming that more than 90% of the 40 tested samples within the reference range <25 ng/mL, the same value as the reference value for prolactin was applied. Since the concentration of monomeric prolactin in serum from which macroprolactin has been removed from blood is diluted 1:1 with PEG, our laboratory is currently reporting the result by multiplying the result by a dilution factor of 2. Conclusion: Radioimmunoassay using PEG precipitation method using the property of precipitating large molecular weight proteins is simple and effective for quantitative measurement of monomeric prolactin in blood prolactin.

FRI314 Prolactinoma And Macroprolactin; A Diagnostic Dilemma

Abstract Disclosure: A. Farooqi: None. S. Dewan: None. J. Jun: None. Prolactin is a 199 amino acid, 23 (Kilo Dalton) kDa protein secreted by pituitary lactotroph cells. The two other major forms of prolactin present in circulation are big prolactin, the dimeric 40-60 kDa prolactin and big-big prolactin or macroprolactin, 100-150 kDa complexes of 23 kDa prolactin and IgG autoantibodies. Hypothalamic dopamine is the primary regulator of prolactin secretion through its inhibitory effect. Prolactinoma accounts for ∼40% of pituitary tumors with clinical presentations of hypogonadotropic hypogonadism and tumor-related mass effects. A 77-year-old female with a past medical history of hypertension and hyperlipidemia was admitted after a mechanical fall. She underwent a computed tomography (CT) of the brain which incidentally showed a pituitary mass. Magnetic resonance imaging (MRI) of pituitary showed a homogenously enhanced 3.0 x 3.5 x 2.8 cm mass centered in the Sella turcica, invading the supra-seller cistern, left cavernous sinus, and orbital apex abutting the optic chiasm and optic tracts. The patient did not report headache, nausea, vomiting, visual changes, or abnormal milky nipple discharge. Physical examination was unremarkable without any neurologic deficit. Formal ophthalmology evaluation showed intact extra ocular movements, visual field-testing using octopus 24-2 and Humphrey test showed few missed points, though not suggestive of pituitary related loss. Serum prolactin was measured at 1432 ng/ml (reference range, 0-25). The presence of macroprolactin was considered due to the absence of clinical features of hyperprolactinemia. The monomeric prolactin was found to be 68.7% (<40%) at 867.5 ng/ml of the total prolactin at 1259.7 ng/ml with 31.3 % of other prolactin forms are present. Evaluation for other pituitary functions was unremarkable with thyroid stimulating hormone (TSH) of 0.72 uIU/ml (0.49-4.76l), morning serum cortisol of 52.9 ug/dl (6.7-22.4), and insulin like growth factor (IGF-1) 73 ng/ml (20-214). Cabergoline 0.5 mg twice weekly was prescribed. This case illustrates a menopausal state as a probable explanation for lack of clinical features of hyperprolactinemia with macro adenoma while macroprolactin should be considered. Presentation: Friday, June 16, 2023

Macroprolactinome géant : à propos d’un cas

The biologically active prolactin is in monomeric form. There are polymerized forms, also called big prolactin and forms linked to immunoglobulins G also called macroprolactin or big big prolactin. We report the case of a 45-year-old patient, operated for prolactin adenoma in 2012.The male macroprolactinoma is a tumor of late discovery, which makes interesting the study of these particularities in order to establish in the light of clinico-biological data and medical imaging therapeutic recommendations and adapted follow-up after consultation between neurosurgeon, endocrinologist and biologist.

Macroprolactin: the Role of Serial Measurement Throughout Pregnancy

Introduction: Prolactin circulates predominantly as a 23 kDa monomer, and a high molecular weight form largely consisting of a complex of prolactin and anti-prolactin IgG autoantibody called macroprolactin. The latter cross-reacts with conventional laboratory assays for prolactin. We here describe the use of serial macroprolactin measurement to assist in the management of a pregnant lady with pre-conception hyperprolactinaemia in whom a magnetic resonance imaging scan had not been performed. Case Report: A 24-year old lady was found to have a raised prolactin level of 2 332 mu/L (reference range: 40–530 mu/L). Prolactin was checked because of primary infertility. Macroprolactin screening was positive, accounting for 54% of measured prolactin (estimated monomeric prolactin=1 073 mu/L). As expected, measured prolactin levels rose through pregnancy to 6 975 mu/L at 20 weeks and to 8 374 mu/L at 36 weeks gestation. Adjustment for macroprolactin and big prolactin gave estimated monomeric prolactin levels of 2 370 mu/L at 16 weeks (macroprolactin/big prolactin=66%), 2 441 mu/L at 20 weeks (macroprolactin/big prolactin=65%) and 2 596 mu/L at 36 weeks (macroprolactin/big prolactin=69%). Thus, adjusted prolactin fell within the reference range for pregnancy at these points. Gel filtration chromatography was performed on the 20-week (second trimester) sample and compared with the pre-pregnancy sample. The pattern remained similar but all components were increased in the second trimester sample (including the monomeric, big prolactin and macroprolactin forms). Conclusion: In this case report, serial measurement of macroprolactin with estimation of monomeric prolactin enhanced clinical management throughout pregnancy, saving unnecessary further investigations and avoiding unnecessary distress for the patient.

Rare Association of Macroprolactinemia and Empty Sella Syndrome

Background: Macroprolactinemia is a polymeric form of prolactin-release, causing mildly symptomatic clinical pictures. The former can be isolated or associated with other causes of hyperprolactinemia. The association with an empty sella syndrome is rare. We report a case of a female patient discovered with this association. Observation: It’s about a female patient 47 years old, followed up since the age of 31 years for bilateral galactorrhea and a spaniomenorrhea. There has been no associated drug intake. Her exploration has showed a serum prolactin level of 635 mIU/L. Thyroid test results were normal T4=10.2 ng/L and TSH=1.76 mIU/L. A brain scan has showed an empty sella turcica. Despite the unchanged levels of prolactinemia, the evolution under dopaminergic 5 mg/D has been marked by the occurrence of a pregnancy with persistent moderate hyperprolactinemia in the postpartum. Chromatography has showed a predominance of the macroprolactin form with: Prolactin monomer at 4.8%, Big Prolactin at 5% and Big Big Prolactin at 83%, thus stopping bromocriptine. Conclusion: Our observation suggests that macroprolactinemia can be associated with conventional etiologies of moderate hyperprolactinemia as the empty sella syndrome. Its detection would prevent the use of dopaminergic therapy which seems not useful.

Lipopolysaccharide induces the expression of an autocrine prolactin loop enhancing inflammatory response in monocytes

BackgroundProlactin from pituitary gland helps maintain homeostasis but it is also released in immune cells where its function is not completely understood. Pleiotropic functions of prolactin (PRL) might be mediated by different isoforms of its receptor (PRLr).MethodsThe aim of this study was to investigate the relationship between the eventual synthesis of PRL and PRLr isoforms with the inflammatory response in monocytes. We used THP-1 and monocytes isolated from healthy subjects stimulated with lipopolysaccharide (LPS). Western blot, real time PCR and immunocytochemistry were performed to identify both molecules. The bioactivity of the PRL was assessed using a bioassay and ELISA to detect pro inflammatory cytokines.ResultsPRLr mRNA and PRL mRNA were synthesized in THP-1 monocytes activated with LPS with peaks of 300-fold and 130-fold, respectively. The long (100 kDa) and the intermediate (50 kDa) isoforms of PRLr and big PRL (60 kDa) were time-dependent upregulated for monocytes stimulated with LPS. This expression was confirmed in monocytes from healthy subjects. The PRLr intermediate isoform and the big PRL were found soluble in the culture media and later in the nucleus in THP-1 monocytes stimulated with LPS. Big PRL released by monocytes showed bioactivity in Nb2 Cells, and both PRL and PRLr, synthesized by monocytes were related with levels of nitrites and proinflammatory citokines.ConclusionsOur results suggest the expression of a full-autocrine loop of PRL enhances the inflammatory response in activated monocytes. This response mediated by big PRL may contribute to the eradication of potential pathogens during innate immune response in monocytes but may also contribute to inflammatory disorders.

Editorial: Is macroprolactinemia just a diagnostic pitfall?

As hyperprolactinemia is involved in the impairment of the gonadotropic axis, serum prolactin (PRL) assessment is often required in the clinical scenario of menstrual disturbances, infertility, loss of libido, galactorrhea, osteoporosis, and bone fractures [1–3]. Nevertheless, the excessive requirement of PRL determination led to an important laboratory pitfall: the find of hyperprolactinemia in subjects with few or no symptoms related to such condition. Human PRL in circulation has marked size heterogeneity, mainly with three forms: 23 kDa (monomeric or little PRL), 50 kDa (dimeric or big PRL), and 150–170 kDa (big–big prolactin or macroprolactin, the three forms being indistinguishable by routine assays [4]. Nevertheless, monomeric PRL, the most common form, is considered to be the biological active one, whereas molecular aggregates as macroprolactin are regarded to have low biologic activity. Therefore, the predominance of macroprolactin, associated with normal levels of monomeric PRL, may lead to the laboratorial diagnosis of hyperprolactinemia in subjects with no symptoms, ending up in unnecessary treatment approaches. The gel-filtration chromatography is the goldstandard method to confirm the presence of big–big PRL, but is a costly and time-consuming process. For routine purposes, precipitation with polyethylene glycol (PEG) is an excellent screening method [5]. The predominant molecular form recovered (i.e., assayed after precipitation) is the highly biologically active monomeric PRL. Usually considering macroprolactin [60% of total PRL, macroprolactinemia has been shown as a common finding, occurring in 8–42% of all cases of hyperprolactinemia. The reason for such large range can be attributed both to selection bias and the use of diverse assays, which differently recognize the amount of big–big PRL in each sample [6]. Macroprolactin biologic activity is still controversial in the literature. Studies in vitro with rat Nb2 cell bioassays show either its presence or absence. To explain the presence of activity in vitro but not in vivo, it was hypothesized that its high molecular weight impairs capillary barrier crossing and its action on target cells. Moreover, the Nb2 cells are a PRL-dependent rat immune cell line expressing a mutant form of PRL receptor, so a bioassay using cells harboring human PRL receptors which addresses the biologic activity of macroprolactin should be more reliable. In fact, a study by Glezer et al. [7] showed that sera of individuals with macroprolactinemia presented lower biological activity in a bioassay using a mouse cell transfected with the long form of human PRL receptor as compared to the rat Nb2 bioassay. Moreover, Hattori et al. [8] assume that the bioactivity of macroprolactin in the Nb2 bioassay is due to dissociation of monomeric PRL from the autoantibodies as a result of the longer incubation than in a bioassay using human breast cancer cells. Despite these controversies in the literature concerning the biologic activity of PRL aggregates, most patients with macroprolactinemia do not manifest clinical features related to hyperprolactinemia. This Endocrine issue brings two publications from Turkey addressing the macroprolactin matter. In one study, Isik et al. [9] enrolled 337 hyperprolactinemic individuals, and found that in 26.1% of them macroprolactinemia prevailed, based on a percentage of PRL in the serum supernatant \40% after PEG precipitation. Subjects with PRL recover value of C40% were considered with absence of M. D. Bronstein (&) Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clinicas, University of Sao Paulo, Sao Paulo, SP, Brazil e-mail: mdbronstein@uol.com.br

Lien physiopathologique entre syndrome des ovaires polymicrokystiques et hyperprolactinémie : mythe ou réalité ?

Polycystic ovary syndrome (PCOS) and hyperprolactinemia are the two most common etiologies of disorders of the cycle in women. In clinical practice, it is not unusual to find hyperprolactinemia associated with clinical, hormonal and ultrasound features of PCOS. However, currently, there is no evidence of a pathophysiological link between these two entities. Thus, this association seems to be fortuitous. Therefore, hyperprolactinemia in women with PCOS must lead to etiological investigations, including eliminating macroprolactinemia (excess of “big prolactin” and/or “big-big prolactin”). Finally, symptomatic hyperprolactinemias (excluding macroprolactinemia) can “mask” an underlying PCOS through a gonadotropic inhibition. Moreover, symptomatic hyperprolactinemias can provide clinical and ultrasound features of a “moderate” PCOS. Therefore, in agreement with the consensus of Rotterdam, PCOS must remain a diagnosis of exclusion, after eliminating symptomatic hyperprolactinemias (excluded macroprolactinemia) and all other etiologies of hyperandrogenism.

Hyperprolactinemia: new assay more specific for the monomeric form does not eliminate screening for macroprolactin with polyethylene glycol precipitation

rolactin presents important size heterogeneity in terms of circulating molecular forms. Besides the monomer (23kDa), which predominates in healthy subjects as well as in patients with prolactinoma, high molecular forms are also present in low concentrations (1). These high molecular forms include 50 kDa dimers (big prolactin) and also forms with even larger molecular weights (MW>150 kDa), known as big-big or macroprolactin. According to our current knowledge, the biological action of pro-lactin is almost exclusively associated with the monomeric form (2). Most of macrop-rolactin is related to the presence of endogenous anti-prolactin antibodies that, acting like a binding protein, prolong the half-life and block receptor binding (3).The practical implication of these facts stems from the observation that in some individuals macroprolactin is the main circulating form, and routine assays for prolac-tin do not distinguish between the different size forms. This phenomenon can lead to misdiagnosis, with important clinical implications, and have been reported by several authors to be present in more than 15% of the patients with hyperprolactinemia (4).Based on cumulative experience it is considered that best practice involves the screening for macroprolactinemia in all samples with hyperprolactinemia. The gold standard to define the presence of macroprolactinemia is gel filtration chromatogra-phy, but due to the expertise and costs involved, more simple alternatives have been developed, with polyethylene glycol (PEG) precipitation being the most used. The technique consists of measurement of prolactin in a serum sample and, when hyper-prolactinemia is present, the sample is submitted to precipitation with PEG solution and the measurement is repeated in the supernatant that contains almost exclusively monomeric prolactin (5).Experience with screening of samples with hyperprolactinemia points to the con-clusion that the best way to describe normal reference ranges for prolactin may be its definition in terms of monomeric values, based on PEG precipitation (6). One additional reason for this position is the fact that different assays (nowadays diffe-rent automatic platforms) recognize macroprolactin differently (7). The ideal solution would be to have assays that do not recognize macroprolactin, so that in the case of hyperprolactinemia one could trust that it represents solely monomeric hyperprolac-tinemia. Several publications have recently described new commercial assays with low recognition of macroprolactin (8-10).

Reporting of Post–PEG Prolactin Concentrations: Time to Change

Prolactin is the hormone most commonly measured in patients evaluated for reproductive disorders. The biologically active form of prolactin is the 23-kDa monomeric polypeptide secreted by the pituitary gland; however, circulating prolactin exists in a number of additional forms. Big prolactin (60 kDa) and macroprolactin (150 kDa), which are present in serum in varying quantities, can cause apparent hyperprolactinemia, but they have no clinical importance because they exhibit little biological activity. Despite efforts to improve assay specificity, all prolactin immunoassays in routine use detect both big prolactin and macroprolactin to varying degrees (1). The polyethylene glycol (PEG) precipitation test is widely used to detect pseudohyperprolactinemia caused by big prolactin and/or macroprolactin. Current best practice recommends that all sera with increased total prolactin concentrations be subfractionated by PEG precipitation to measure the bioactive monomeric prolactin concentration, a more clinically meaningful variable (2)(3). Subfractionation with PEG allows laboratories to distinguish patients with true hyperprolactinemia, in which there are supraphysiological concentrations of bioactive monomeric prolactin, from those with macroprolactinemia, which is characterized by increased concentrations of macroprolactin and/or big prolactin together with normal concentrations of bioactive monomeric prolactin. In the absence of PEG screening, misdiagnosis and consequent …

PROLACTIN PROFILES AND THEIR MOLECULAR WEIGHTS IN SERUM AND TISSUES OF PATIENTS WITH UTERINE LEIOMYOMA IN IRAQ

Background: Uterine leiomyomas are benign tumors arising from the myometrial compartment of the uterus. They are the most common gynecologic neoplasm, occurring with a remarkable frequency in more than 70% of women at their reproductive age. The female reproductive tract is known to be an extrapituitary source of the hormone prolactin. Prolactin (PRL) is a polypeptide hormone of growth hormone/cytokine family. In serum, PRL occurs in various molecular forms with different molecular weights, including the physiologically active monomeric form called the little PRL, the big PRL, and the big big PRL, that is also called macroprolactin. Objectives: To study the PRL profiles with its molecular weights in patient’s serum, leiomyomas, and myometrium compared with the PRL profiles of a normal myometrium. Subjects and methods: Circulating prolactin of patient group (n=57) as well as their tissues prolactin [(leiomyomas and myometrium)] and [normal myometrium] of the control group (n=45) was assayed using the Prolactin Kit (Biomerieux). Prolactin profile was detected using the polyethylene glycol 8000 precipitating method to separate the big big prolactin from the monomeric and the big prolactin isoforms. Disk gel electrophoresis technique was used to confirm the prolactin isoforms and to calculate their molecular weights. Results: A highly significant difference was found between the leiomyoma prolactin and patient's myometrium prolactin as well as between the leiomyoma prolactin and the normal myometrium prolactin (P<0.0001), while no significance was found between patient’s myometrium and the normal myometrium prolactin. Also a high significance (P<0.0001) was found between the patients serum prolactin and their leiomyoma prolactin, leiomyoma size, while a significant value (P<0.05) was found between leiomyoma prolactin and their sizes. In this study the prolactin isoforms in patient’s serum, leiomyoma and myometrium as well as in the normal myometrium of control group were monomeric and big prolactin with different molecular weights. Only one sample of patient’s serum had big big prolactin isoform. Conclusion: Serum prolactin level was increased in patient with uterine leiomyoma with a significant positive correlation with the leiomyoma size and its prolactin produced from it. Hyperprolactinemia may be also caused by macroprolactin in patients with uterine leiomyoma because the big forms of PRL have a decreased bioactivity, they do not cause clinical symptoms of hyperprolactinemia.

Macroprolactinemia in childhood and adolescence: a cause of hyperprolactinemia

Human prolactin consists of multiple forms of different sizes including three major prolactin (PRL) species, termed as little, big, and big-big PRL. If serum contains big-big PRL, it is termed macroprolactinemia; no symptoms of hyperprolactinemia develop due to low biological activity of big-big PRL. There are still few data regarding macroprolactinemia in children and adolescents. In this paper we describe six patients with macroprolactinemia, one of whom was asymptomatic and the other five either had headache, menstrual disturbance, short stature, increased hair growth or early puberty, compatible with high PRL levels. Two of the cases had microadenoma. Initial mean +/- SD PRL levels of the patients were 75.2 +/- 22.8 ng/ml (range: 42.3-105.2 ng/ml). Macroprolactin analysis revealed big-big PRL levels of the patients ranging between 21.6-98.6 ng/ml. It was noteworthy that bromocriptine (BRC) therapy started in three patients caused an abrupt decrease in PRL levels. It may be concluded that macroprolactinemia should be taken into account in the differential diagnosis of hyperprolactinemia in childhood and adolescence, whether or not they have relevant clinical symptoms.

Serum free prolactin concentrations in patients with systemic lupus erythematosus are associated with lupus activity

To determine in patients with systemic lupus erythematosus (SLE) the relationships among serum total and free prolactin (PRL) levels, isoforms of PRL and lupus activity. In a cross-sectional study, 259 patients with SLE were tested for serum total PRL, serum free PRL, and PRL in fractions obtained after gel filtration chromatography (in 70 sera taken at random) by immunoradiometric assay based on disease activity. A significant correlation between direct PRL and free PRL levels was found in patients with and without lupus activity (r = 0.475, P<0.001); however, this was less so for non-active patients than for active patients (r=0.433, P<0.001 and r=0.909, P<0.001, respectively). SLE Disease Activity Index (SLEDAI) scores correlated positively with serum free PRL levels (r=0.314, P<0.001) and percentage of little PRL (r=0.33, P=0.005) and negatively with percentage of big big PRL (r=-0.3, P=0.012). Patients with active disease had higher serum free PRL levels (median 12.6 vs 9.3 ng/ml, P<0.001), higher percentages of little PRL (83.1 +/- 21.2 vs 63.6 +/- 24.8%, P=0.011) and lower percentages of big big PRL (9.4 +/- 18.0 vs 25.2 +/- 24.3%, P=0.031). Different clinical manifestations and serological parameters of lupus disease activity were more frequent in patients with free hyperprolactinaemia than in patients with normal serum free PRL levels (such as neurological manifestations, renal involvement, serositis, haematological manifestations, anti-double-stranded DNA and hypocomplementaemia; P<0.021). An increase in serum free PRL levels, higher percentages of little PRL and lower percentages of big big PRL proved to be factors related to lupus activity in a subset of patients with SLE. These novel data must be taken into account in future studies aiming to establish a relationship between PRL and disease activity in SLE.

Immunoprecipitation for Rapid Detection of Macroprolactin in the Form of Prolactin–Immunoglobulin Complexes

The 3 major forms of serum prolactin (PRL), identifiable by gel-filtration chromatography (GFC), are monomeric PRL (23 kDa), big PRL (45–60 kDa), and big, big PRL or macroprolactin (150–170 kDa) (1). The common macroprolactin is PRL complexed with human IgG, but aggregates of PRL, some extensively glycosylated, may also occur (2)(3)(4)(5)(6). Macroprolactin has slower serum clearance than monomeric PRL and little or no apparent in vivo bioactivity, probably because it does not cross capillary walls (7)(8). Macroprolactin causes diagnostic confusion in evaluating hyperprolactinemia (9)(10). Polyethylene glycol (PEG) precipitation is a rapid screening method for macroprolactinemia (11)(12)(13)(14)(15)(16)(17), but PEG interference with PRL assays limits its general use. The method, moreover, shows nonspecific precipitation (up to 15%), necessitating use of a gray zone. We recently validated a screening method based on recognition of the IgG component of macroprolactin by anti-IgG-agarose (18); this method, however, had insufficient PRL assay sensitivity for use in moderate hyperprolactinemia (PRL <1000 mIU/L). A more rapid screening method based on PRL-IgG precipitation with protein A-Sepharose was described recently (19). We report a simple, rapid method, also based on precipitation of PRL-IgG complexes, with protein G-agarose (PGA) suspension and high IgG binding capacity (20 mg/mL of resin). The protein G polypeptide binds the Fc region of all subclasses of the human IgG molecule and also binds the IgG3 fraction (20). Results with this method were compared with those from GFC and PRL-PEG precipitation. For GFC, we used the fast FPLC system (Pharmacia) with a Superdex 200 HR10/300 prepacked column (Amersham Pharmacia) (11). Serum (100 μL) was applied and eluted with phosphate-buffered saline (PBS; 0.05 mol/L, pH 7.0) at a flow rate of …

Macroprolactin; high molecular mass forms of circulating prolactin

Two high molecular mass forms of prolactin (PRL) in serum have been identified by gel filtration chromatography (GFC): macroprolactin (big-big PRL, > 100 kDa) and big PRL (40-60 kDa). Macroprolactin has a variable composition and structure, but is most frequently a complex of PRL and IgG, with a molecular mass of 150-170 kDa. It is formed in the circulation following pituitary secretion of monomeric PRL but has a longer half-life, and the PRL in the complex remains reactive to a variable extent in immunoassays. In the majority of subjects little or no macroprolactin can be detected in serum, but in some individuals it may be the predominant immunoreactive component of circulating PRL and the cause of apparent hyperprolactinaemia. Owing to its high molecular mass, macroprolactin appears to be confined to the intravascular compartment and much evidence indicates that it has minimal bioactivity in vivo and is not of pathological significance. Nevertheless, hyperprolactinaemia due to macroprolactin can lead to diagnostic confusion and unnecessary further investigation and treatment if it is not recognized as such. Macroprolactin is a common cause of apparent hyperprolactinaemia with some assays and it is essential that laboratories introduce screening programmes to examine samples with elevated total immunoreactive PRL for the presence of macroprolactin and determine the monomeric PRL component which is known to be bioactive in vivo. A number of screening tests have been described; that based on the precipitation of macroprolactin with polyethylene glycol has been the most widely validated and applied. The reference technique of GFC should be available for confirmation and further investigation of samples, giving equivocal results in screening tests. In comparison with macroprolactin, little is known about big PRL. It is a more consistent component of total serum PRL but rarely, if ever, the cause of hyperprolactinaemia. Further research is required into the nature of macroprolactin and big PRL, the relationships between high molecular mass forms of PRL, and their clinical significance.

L'IRM hypophysaire : indications et résultats en gynécologie et en obstétrique

MRI is the sole radiological examination to be obtained if abnormal menses, galactorrhea or anovulation evokes the diagnosis of prolactinoma. Nevertheless, iatrogenic hyperprolactinemia or presence of big prolactin has to be ruled out before MRI is asked for. MRI of the pituitary gland must be technically optimal; analysis of the images has to be directed by clinical and biological data.

The Clinical Characteristics of Macroprolactinemia

Background: Prolactin has been identified by gel chromatography to exist is three different forms in human serum; monomeric prolactin (molecular mass 23 kDa), big prolactin (molecular mass 50~60 kDa) and big big prolactin, otherwise known as macroprolactin (molecular mass 150~170 kDa). The predominance of macroprolactinemia has long been known in idiopathic hyperprolactinemic patients with maintained fertility. In recent reports, 24% of microprolactinoma patients showed no menstrual disturbances, which was suggestive of macroprolactinemia. The purpose of this study was to evaluate: (1) the frequency of macroprolactinemia among idiopathic hyperprolactinemia and prolactinoma patients, (2) the difference in the clinical characteristics between hyperprolactinemia, with and without macroprolactinemia, among idiopathic hyperprolactinemia and prolactinoma patients, and (3) the follow-up prolactin level using the bromocriptine response. Methods: We retrospectively analyzed the clinical characteristics and prolactin levels in 43 idiopathic hyperprolactinemia and 51 prolactinoma patients with a poor bromocriptine response. Macroprolactinemia was identified by the prolactin recovery of < 40% using the polyethylene glycol (PEG) precipitation test. Results: (1) Of the 43 idiopathic hyperprolactinemia and 51 prolactinoma patients, 17 (39.5%) and 9 (17.6%), respectively, were macroprolactinemic (P < 0.05). (2) Among the idiopathic hyperprolactinemia patients, galactorrhea combined with amenorrhea was significantly less frequent (P < 0.05), with the 1- and 2-year follow-up prolactin levels being significantly higher in those with macroprolactinemia than monomeric prolactinemia (P <0 .05). (3) Among the prolactinoma patients, amenorrhea was significantly less frequent (P < 0.05), but asymptomatic cases were more frequent in those with macroprolactinemia than monomeric prolactinemia (P < 0.05). The 1and 2-year follow-up prolactin levels were significantly higher in those with macroprolactinemia than monomeric prolactinemia (P < 0.05). Conclusion: The screening of macroprolactinemia should be considered in idiopathic hyperprolactinemia and prolactinoma patients with a poor bromocriptine response (J Kor Soc Endocrinol 20:216～223, 2005).

Hyperprolactinaemia and the regular menstrual cycle in asymptomatic women: should it be treated during therapy for infertility?

It is known that hyperprolactinaemia can cause galactorrhoea and irregular cycles or even amenorrhoea. High serum prolactin (PRL) can disturb follicular maturation and corpus luteum function. Treatment of hyperprolactinaemia in patients with resulting bleeding anomalies is established, but the question is how to manage normal cyclic hyperprolactinaemic women? Studies have shown that in a subgroup of asymptomatic patients the serum contains mainly high molecular weight form (big big PRL), which has a low bioactivity, called macroprolactinaemia. It is evident that macroprolactin does not affect the control of pituitary PRL secretion via the short loop feedback mechanism or the secretion of gonadotrophins as does monomeric PRL. Identification of macroprolactinaemia is therefore clinically important to prevent unnecessary examinations and inappropriate treatment. Prolactinoma can be associated with macroprolactinaemia. Performance of pituitary imaging in asymptomatic patients with hyperprolactinaemia may therefore be justified, but further studies are needed to evaluate the relation of costs and benefit. An unsolved problem is the differentiation between inactive and PRL-secreting tumours. Caution should be exercised concerning medical treatment in unstimulated patients and also in patients during ovarian stimulation alone or in combination with intrauterine insemination or in-vitro fertilization. The potential clinical significance of hyperprolactinaemia/macroprolactinaemia in asymptomatic women must be further evaluated.

Estimation de la prolactine monomérique après précipitation du sérum au polyéthylène glycol (PEG)

Macroprolactin or big-big prolactin, is a high molecular weight prolactin-IgG complex which is, at least partly, measured by commercial immunoassays and can cause hyperprolactinemia. Polyethylene glycol (PEG) precipitation eliminates macroprolactin from serum but can also partly precipitate monomeric prolactin and big prolactin. Regarding monomeric prolactin measurements in the PEG supernatant, a specific threshold of hyperprolactinemia has to be determined. We measured prolactin with the Elecsys assay before and after, volume by volume, 25% PEG precipitation in 284 sera without hyperprolactinemia (prolactin <600 mIU/L) and without macroprolactinemia (PEG precipitation <40%). Monomeric prolactin was estimated by multiplying the prolactin measured in the PEG supernatant by 2. We also studied 178 hyperprolactinemic sera with macroprolactin (PEG precipitation >60%). The hyperprolactinemia threshold obtained from the 284 control sera was 475 mIU/L. Out of the 178 hyperprolactinemic sera, 16% had monomeric prolactin concentrations over this threshold. In conclusion, macroprolactin is not always the sole cause of hyperprolactinemia and monomeric prolactin should be estimated to avoid misdiagnosis.

Frequent misdiagnosis and mismanagement of hyperprolactinemic patients before the introduction of macroprolactin screening: application of a new strict laboratory definition of macroprolactinemia.

Macroprolactin (big big prolactin) has reduced bioactivity and is measured by immunoassays for prolactin when it accumulates in the plasma of some individuals. We applied normative data for serum prolactin after treatment of sera to remove macroprolactin to elucidate the contribution of macroprolactin to misleading diagnoses, inappropriate investigations, and unnecessary treatment. We reviewed records of women attending a tertiary referral center who had prolactin >1000 mIU/L. Application of a reference interval to polyethylene glycol (PEG)-treated hyperprolactinemic sera identified 21 patients in whom hyperprolactinemia was accounted for entirely by the presence of macroprolactin. Presenting clinical features, diagnoses, and treatment were compared in these patients and 42 age-matched true hyperprolactinemic patients. Prolactin concentrations in sera of 110 healthy individuals ranged from 78 to 564 mIU/L. The range of values for the sera after PEG treatment was 70-403 mIU/L. For macroprolactinemic samples, PEG treatment decreased mean (SD) prolactin from 1524 (202) mIU/L to 202 (27) mIU/L but decreased it only from 2096 (233) mIU/L to 1705 (190) mIU/L in true hyperprolactinemic patients (P <0.01 between groups). Oligomenorrhea or amenorrhea and galactorrhea were the most common clinical features in both groups, although they occurred more frequently in true hyperprolactinemic patients (P <0.05). Serum estradiol and luteinizing hormone concentrations were significantly higher in participants with macroprolactinemia than in those with true hyperprolactinemia (P <0.05). Among participants with retrospectively identified macroprolactinemia, pituitary imaging was performed in 93% and treatment with dopamine agonist was prescribed in 87%. Macroprolactin is a significant cause of misdiagnosis, unnecessary investigation, and inappropriate treatment. The use of an appropriate reference interval for the PEG immunoprecipitation procedure may be of particular importance in those patients who have an excess of both macroprolactin and monomeric prolactin.