Macroprolactin: From laboratory to clinical practice.

Prolactin measurement is very common in standard clinical practice. It is indicated not only in the study of pituitary adenomas, but also when there are problems with fertility, decreased libido, or menstrual disorders, among other problems. Inadequate interpretation of prolactin levels without contextualizing the laboratory results with the clinical, pharmacological, and gynecological/urological history of patients leads to erroneous diagnoses and, thus, to poorly based studies and treatments. Macroprolactinemia, defined as hyperprolactinemia due to excess macroprolactin (an isoform of a greater molecular weight than prolactin but with less biological activity), is one of the main causes of such erroneous diagnoses, resulting in poor patient management when not recognized. There is no unanimous agreement as to when macroprolactin screening is required in patients with hyperprolactinemia. At some institutions, macroprolactin testing by polyethylene glycol (PEG) precipitation is routinely performed in all patients with hyperprolactinemia, while others use a clinically based approach. There is also no consensus on how to express the results of prolactin/macroprolactin levels after PEG, which in some cases may lead to an erroneous interpretation of the results. The objectives of this study were: 1. To establish the strategy for macroprolactin screening by serum precipitation with PEG in patients with hyperprolactinemia: universal screening versus a strategy guided by the alert generated by the clinician based on the absence or presence of clinical symptoms or by the laboratory when hyperprolactinemia is detected. 2. To create a consensus document that standardizes the reporting of prolactin results after precipitation with PEG to minimize errors in the interpretation of the results, in line with international standards.

Macroprolactin: From laboratory to clinical practice. / Macroprolactina: del laboratorio a la práctica clínica. Recomendaciones del grupo de trabajo de laboratorio de la SEEN y de la comisión de hormonas de la SEQCML sobre la medición e informe del resultado de la macroprolactina.

Prolactin measurement is very common in standard clinical practice. It is indicated not only in the study of pituitary adenomas, but also when there are problems with fertility, decreased libido, or menstrual disorders, among other problems. Inadequate interpretation of prolactin levels without contextualizing the laboratory results with the clinical, pharmacological, and gynecological/urological history of patients leads to erroneous diagnoses and, thus, to poorly based studies and treatments. Macroprolactinemia, defined as hyperprolactinemia due to excess macroprolactin (an isoform of a greater molecular weight than prolactin but with less biological activity), is one of the main causes of such erroneous diagnoses, resulting in poor patient management when not recognized. There is no unanimous agreement as to when macroprolactin screening is required in patients with hyperprolactinemia. At some institutions, macroprolactin testing by polyethylene glycol (PEG) precipitation is routinely performed in all patients with hyperprolactinemia, while others use a clinically based approach. There is also no consensus on how to express the results of prolactin/macroprolactin levels after PEG, which in some cases may lead to an erroneous interpretation of the results. The objectives of this study were: 1. To establish the strategy for macroprolactin screening by serum precipitation with PEG in patients with hyperprolactinemia: universal screening versus a strategy guided by the alert generated by the clinician based on the absence or presence of clinical symptoms or by the laboratory when hyperprolactinemia is detected. 2. To create a consensus document that standardizes the reporting of prolactin results after precipitation with PEG to minimize errors in the interpretation of the results, in line with international standards.

Valores de referencia de TSH en población gestante española. ¿Podemos unificar criterios? / Reference TSH levels in Spanish pregnant women. Is it possible to unify criteria?

Introducción: Durante la gestación, se requieren rangos de referencia específicos de TSH y de tiroxina libre para la correcta valoración de la función tiroidea materna. Objetivo: Revisión de estudios sobre valores de referencia para TSH y tiroxina libre durante el primer trimestre de gestación de población española. Material y métodos: Búsqueda bibliográfica y selección de estudios que contengan rangos de referencia de TSH en el primer trimestre de gestación. Resultados: El punto de corte de TSH para definir hipotiroidismo (P97,5) varió según el inmunoanálisis utilizado. La edad gestacional, la autoinmunidad tiroidea y el estado nutricional de yodo de las poblaciones utilizadas condicionaron la variación observada en los resultados. Conclusiones: Las diferencias encontradas en los estudios revisados no permiten establecer un rango de referencia unificado para TSH. No obstante, se observa que el límite superior del rango para TSH está próximo a 4μU/mL. Sería conveniente disponer de rangos de referencia propios para cada población y específicos para cada inmunoanálisis

Introduction: Specific TSH and free thyroxine ranges are needed to adequately assess maternal thyroid function during pregnancy. Aim: The aim of this review is to review studies reporting data on references TSH and free thyroxine levels in Spanish women during the first trimester of pregnancy. Material and methods: Literature search and selection of studies providing reference TSH ranges in the first trimester of pregnancy. Results: The TSH cut-off point to define hypothyroidism (P97.5) was different depending on the immunoassay used. Gestational age, thyroid autoimmunity, and maternal iodide nutritional status can determine the variability seen in the results. Conclusions: Differences found in the studies do not allow for establishing a unified TSH reference range. However, results suggest that the TSH upper reference limit is close to 4μU/mL. Reference TSH ranges specific for each population and immunoassay during pregnancy should be defined

Reference TSH levels in Spanish pregnant women. Is it possible to unify criteria? / Valores de referencia de TSH en población gestante española. ¿Podemos unificar criterios?

INTRODUCTION: Specific TSH and free thyroxine ranges are needed to adequately assess maternal thyroid function during pregnancy. AIM: The aim of this review is to review studies reporting data on references TSH and free thyroxine levels in Spanish women during the first trimester of pregnancy. MATERIAL AND METHODS: Literature search and selection of studies providing reference TSH ranges in the first trimester of pregnancy. RESULTS: The TSH cut-off point to define hypothyroidism (P97.5) was different depending on the immunoassay used. Gestational age, thyroid autoimmunity, and maternal iodide nutritional status can determine the variability seen in the results. CONCLUSIONS: Differences found in the studies do not allow for establishing a unified TSH reference range. However, results suggest that the TSH upper reference limit is close to 4µU/mL. Reference TSH ranges specific for each population and immunoassay during pregnancy should be defined.

[Impact of the application of the American Thyroid Association criteria on the diagnosis of hypothyroidism in pregnant women in Vigo, Spain]. / Impacto de la aplicación de los criterios de la asociación americana de tiroides en el diagnóstico de hipotiroidismo en gestantes de Vigo, España.

In order to determine the impact of the application of the American Thyrold Associations (ATA) criteria for the diagnosis of hypothyroidism in pregnant women in the health district of Vigo, Spain, concentrations of serum thyrotropin (TSH), free thyroxine (T4L) and anti-thyroid antibodies were analyzed, comparing the frequency of pregnant women diagnosed with hypothyroidism and applying the criteria used in the hormone laboratory at Xeral Hospital and referential criteria established by ATA. The application of ATA referential criteria increased by 29.6% the number of female patients diagnosed with hypothyroidism. The application of ATA guidelines had an impact on the measurement of TSH concentrations in pregnant women, which calls for an evaluation of referential values of TSH based on the population and the local diagnostic methods.

Impacto de la aplicación de los criterios de la Asociación Americana de Tiroides en el diagnóstico de hipotiroidismo en gestantes de Vigo, España / Impact of the application of the American Thyroid Association criteria on the diagnosis of hypothyroidism in pregnant women in Vigo, Spain

Con el objetivo de determinar el impacto de la aplicación de los criterios de la Asociación Americana de Tiroides (ATA) en el diagnóstico de hipotiroidismo en gestantes del área sanitaria de Vigo en España, se analizó la concentración sérica de tirotropina (TSH), tiroxina libre (T4L) y anticuerpos antitiroideos, comparando la frecuencia de gestantes diagnosticadas de hipotiroidismo aplicando los criterios utilizados en el laboratorio de hormonas del Hospital Xeral y los criterios de referencia propuestos por la ATA. La asunción de dichos criterios implicaría un aumento de un 29,6% de pacientes diagnosticadas de hipotiroidismo. La aplicación de los criterios ATA tuvo una repercusión en la medición de la concentración de TSH en gestantes lo que sugiere una evaluación de los valores de referencia de TSH en función de la población y los métodos de diagnóstico locales.

In order to determine the impact of the application of the American Thyrold Associations (ATA) criteria for the diagnosis of hypothyroidism in pregnant women in the health district of Vigo, Spain, concentrations of serum thyrotropin (TSH), free thyroxine (T4L) and anti-thyroid antibodies were analyzed, comparing the frequency of pregnant women diagnosed with hypothyroidism and applying the criteria used in the hormone laboratory at Xeral Hospital and referential criteria established by ATA. The application of ATA referential criteria increased by 29.6% the number of female patients diagnosed with hypothyroidism. The application of ATA guidelines had an impact on the measurement of TSH concentrations in pregnant women, which calls for an evaluation of referential values of TSH based on the population and the local diagnostic methods.

Cromogranina A. La familia cromogranina-secretogranina / Chromogranin-A. The chromogranin-secretogranin family

Las cromograninas A y B, y la secretogranina II constituyen los principales miembros de una familia de proteínas solubles, las graninas, localizadas en la matriz de los gránulos secretorios de la mayoría de las células neuroendocrinas, y que incluyen también a las menos conocidas secretograninas III-VII. Aunque genéticamente diferentes, se caracterizan por compartir almacenamiento y secreción con otras hormonas y péptidos en las células del sistema neuroendocrino difuso, participar activamente en el proceso de formación del gránulo secretorio y presentar numerosos puntos para su procesamiento proteolítico por las enzimas PC1/3 y PC2, coalmacenadas también en el gránulo secretorio, y dar lugar a péptidos con propiedades reguladoras, funcionando así comoprohormonas. Las graninas, en general, y la cromogranina A, en particular, tendrían, así,3 funciones principales: a) papel intracelular crucial en la formación de los gránulos de secreción y en la liberación de hormonas y neurotransmisores en las células neuroendocrinas; b) comoprohormonas, a nivel extracelular, siendo precursores de varios péptidosbioactivos derivado de su procesamiento proteolítico, actuando de forma autocrina, paracrina y endocrina, y c) papel como marcador no específico,concretamente la cromogranina A, en el manejo de neoplasiasneuroendocrinas (AU)

Chromogranin A (CgA), B (CgB) and secretogranin II (SgII) are the principal members of a family of soluble proteins called granins, which are found in thematrix of the secretory granules of the majority of neuroendocrine cells, and which also include the lesser known secretogranins III - VII. Although genetically different, they are characterized by sharing storage and secretion with other hormones and peptides in the cells of the diffuse neuroendocrine system, actively participating in secretory granule formation, with numerous sites for the proteolytic enzymes PC1/3 and PC2, which are also stored in the secretory granule, and producing peptides with regulatory properties, thus functioning as prohormones. Therefore, granins in general, and CgA in particular, should have three main functions: a crucial intracellular role insecretory granule formation and hormone and neurotransmitter release in the neuroendocrine cells: b) as pro-hormones, at extracellular level, due to being the precursors of several bioactive peptides produced by their proteolytic process, having autocrine, paracrine and endocrine functions; and c) a role as a non-specificmarker, particularly chromogranin A, in the management of neuroendocrine neoplasias (AU)

Significación clínica de la macroprolactina / Clinical significance of macroprolactin

Introducción: La macroprolactina (maPRL) es una variedad molecular de prolactina (PRL) de alto peso molecular y de actividad biológica cuestionable. El objetivo del presente estudio fue valorar la repercusión clínico-analítica de la presencia de maPRL en pacientes con hiperprolactinemia. Pacientes y método: Seleccionamos las muestras con concentraciones de PRL > 50 ng/ml (1.060 MU/l), tras la realización de la técnica de precipitación con polietilenglicol (PEG) 6000, consideramos que presentaban maPRL aquellas con valores de recuperación 50 ng/ml estudiados en un periodo de 24 meses, 22 presentaron maPRL (9,6%), todas mujeres con edad media de 32 años (12-48). El rango de PRL basal fue de 50,5 a 158 ng/ml. El motivo más frecuente de petición de PRL fueron las alteraciones menstruales (el 45% de los pacientes). Para valorar la repercusión clínica, evaluamos la PRL monomérica en estas pacientes y encontramos que en el 36,4% la maPRL se asociaba a aumento de PRL monomérica (grupo A) y en este grupo presentaba clínica hipogonadal el 87,5%. La maPRL se asociaba con concentraciones fisiológicas de PRL monomérica en el 63,6% (grupo B) y en este grupo presentaba clínica de amenorrea sólo 1 (7,14%) paciente, p < 0,05. De las 6 pacientes a las que se realizó estudio radiológico, 2 presentaron adenomas. Se trató con agonistas dopaminérgicos a 6 pacientes y en todas se normalizaron la clínica y los valores de hiperprolactinemia. Conclusiones: En nuestra serie, la presencia de maPRL sólo se acompañó de clínica de disfunción gonadal cuando se asoció a hiperprolactinemia monomérica. La maPRL aislada carece de significado clínico, pero es importante determinarla para evitar un manejo clínico innecesario

Introduction: Macroprolactin (maPRL) is a high molecular weight variant of prolactin (PRL) with reduced bioactivity. The purpose of the present study was to determine the clinical-laboratory repercussions of the presence of maPRL in patients with hyperprolactinemia. Patients and Method: A polyethylene glycol (PEG) precipitation test was used to detect the presence of maPRL in all consecutive samples with a prolactin concentration of > 50 ng/ml (1.060 MU/l). A recovery 50 ng/ml. All the patients with maPRL were women; the mean age was 32 years (12-48). Serum PRL levels ranged from 50.5-158 ng/ml. The most frequent reason for the initial PRL request was menstrual disturbance (45% patients). To study clinical repercussions, monomeric PRL was determined. The results showed that maPRL was associated with an increase of monomeric PRL levels in 36.4% of the patients (group A) and that 87.5% of patients in this group had hypogonadal symptoms. MaPRL was associated with physiological concentrations of monomeric PRL in 63.6% (group B) and only one patient in this group had amenorrhea (7.14%), p < 0.05. Of 6 patients who underwent neuroimaging, pituitary adenomas were identified in 2. Six patients were treated with dopamine agonists. In all 6 of these patients, symptoms and hyperprolactinemic values were resolved. Conclusions: Our results indicate that patients with maPRL only presented symptomatology suggestive of hyperprolactinemia when the monomeric PRL concentration was elevated. MaPRL has limited clinical repercussions but its determination in routine practice is important to avoid inappropriate management