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      Controversial issues in the management of hyperprolactinemia and prolactinomas – An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism

      review-article
      1 , 2 , 1 , 3 , 4 , 5 , 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 8 , 13 , 8 , 13 , 14 , 13 , 6 , 4 , 15 , 10 , 7 , 8
      Archives of Endocrinology and Metabolism
      Sociedade Brasileira de Endocrinologia e Metabologia
      Hyperprolactinemia, prolactinomas, pseudoprolactinomas, macroprolactin, hook-effect, dopamine agonists, pituitary surgery, temozolomide

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          ABSTRACT

          Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called “hook effect”. Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.

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          Most cited references274

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          High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium.

          Prevalence data are important for assessing the burden of disease on the health care system; data on pituitary adenoma prevalence are very scarce. The objective of the study was to measure the prevalence of clinically relevant pituitary adenomas in a well-defined population. This was a cross-sectional, intensive, case-finding study performed in three regions of the province of Liège, Belgium, to measure pituitary adenoma prevalence as of September 30, 2005. The study was conducted in specialist and general medical practitioner patient populations, referral hospitals, and investigational centers. Three demographically and geographically distinct districts of the province of Liège were delineated precisely using postal codes. Medical practitioners in these districts were recruited, and patients with pituitary adenomas under their care were identified. Diagnoses were confirmed after retrieval of clinical, hormonal, radiological, and pathological data; full demographic and therapeutic follow-up data were collected in all cases. Sixty-eight patients with clinically relevant pituitary adenomas were identified in a population of 71,972 individuals; the mean (+/- sd) prevalence was 94 +/- 19.3 cases per 100,000 population (95% confidence interval, 72.2 to 115.8). The group was 67.6% female and had a mean age at diagnosis of 40.3 yr; 42.6% had macroadenomas and 55.9% underwent surgery. Prolactinomas comprised 66% of the group, with the rest having nonsecreting tumors (14.7%), somatotropinomas (13.2%), or Cushing's disease (5.9%); 20.6% had hypopituitarism. The prevalence of pituitary adenomas in the study population (one case in 1064 individuals) was more than 3.5-5 times that previously reported. This increased prevalence may have important implications when prioritizing funding for research and treatment of pituitary adenomas.
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            Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline.

            The aim was to formulate practice guidelines for the diagnosis and treatment of hyperprolactinemia. The Task Force consisted of Endocrine Society-appointed experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society, The European Society of Endocrinology, and The Pituitary Society reviewed and commented on preliminary drafts of these guidelines. Practice guidelines are presented for diagnosis and treatment of patients with elevated prolactin levels. These include evidence-based approaches to assessing the cause of hyperprolactinemia, treating drug-induced hyperprolactinemia, and managing prolactinomas in nonpregnant and pregnant subjects. Indications and side effects of therapeutic agents for treating prolactinomas are also presented.
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              Advances in the treatment of prolactinomas.

              Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.
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                Author and article information

                Journal
                Arch Endocrinol Metab
                Arch Endocrinol Metab
                aem
                Archives of Endocrinology and Metabolism
                Sociedade Brasileira de Endocrinologia e Metabologia
                2359-3997
                2359-4292
                23 March 2018
                Mar-Apr 2018
                : 62
                : 2
                : 236-263
                Affiliations
                [1 ] normalizedUniversidade Federal de Pernambuco orgnameUniversidade Federal de Pernambuco orgdiv1Hospital das Clínicas orgdiv2Serviço de Endocrinologia Recife PE Brasil originalServiço de Endocrinologia, Hospital das Clínicas, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brasil
                [2 ] normalizedUniversidade Federal de São Paulo orgnameUniversidade Federal de São Paulo orgdiv1Escola Paulista de Medicina orgdiv2Unidade de Neuroendócrino São Paulo SP Brasil originalUnidade de Neuroendócrino, Escola Paulista de Medicina, Universidade Federal de São Paulo (Unifesp/EPM), São Paulo, SP, Brasil
                [3 ] orgnameCentro de Endocrinologia e Diabetes de Joinville Joinville SC Brasil originalCentro de Endocrinologia e Diabetes de Joinville (Endoville), Joinville, SC, Brasil
                [4 ] normalizedUniversidade de Brasília orgnameUniversidade de Brasília orgdiv1Hospital Universitário de Brasília orgdiv2Serviço de Endocrinologia Brasília DF Brasil originalServiço de Endocrinologia do Hospital Universitário de Brasília, Universidade de Brasília (UnB), Brasília, DF, Brasil
                [5 ] normalizedUniversidade Federal do Paraná orgnameUniversidade Federal do Paraná orgdiv1Hospital de Clínicas orgdiv2Serviço de Endocrinologia e Metabologia Curitiba PR Brasil originalServiço de Endocrinologia e Metabologia, Hospital de Clínicas, Universidade Federal do Paraná (SEMPR), Curitiba, PR, Brasil
                [6 ] normalizedUniversidade de São Paulo orgnameUniversidade de São Paulo orgdiv1Faculdade de Medicina orgdiv2Divisão de Neurocirurgia Funcional, Instituto de Psiquiatria do Hospital das Clínicas São Paulo SP Brasil originalDivisão de Neurocirurgia Funcional, Instituto de Psiquiatria do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (IPq-HC-FMUSP), São Paulo, SP, Brasil
                [7 ] normalizedUniversidade Federal do Rio Grande do Sul orgnameUniversidade Federal do Rio Grande do Sul orgdiv1Faculdade de Medicina orgdiv2Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, PPG Endocrinologia Porto Alegre RS Brasil originalServiço de Endocrinologia, Hospital de Clínicas de Porto Alegre, PPG Endocrinologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brasil
                [8 ] orgnameFaculdade de Medicina da Universidade de São Paulo orgdiv1Hospital das Clínicas orgdiv2Serviço de Endocrinologia São Paulo SP Brasil originalServiço de Endocrinologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brasil
                [9 ] normalizedUniversidade Federal do Maranhão orgnameUniversidade Federal do Maranhão orgdiv1Hospital Universitário Presidente Dutra orgdiv2Serviço de Endocrinologia São Luís MA Brasil originalServiço de Endocrinologia, Hospital Universitário Presidente Dutra, Universidade Federal do Maranhão (UFMA), São Luís, MA, Brasil
                [10 ] normalizedUniversidade Federal do Rio de Janeiro orgnameUniversidade Federal do Rio de Janeiro orgdiv1Hospital Universitário Clementino Fraga Filho orgdiv2Serviço de Endocrinologia Rio de Janeiro RJ Brasil originalServiço de Endocrinologia, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro (HUCFF-UFRJ), Rio de Janeiro, RJ, Brasil
                [11 ] normalizedInstituto Estadual do Cérebro Paulo Niemeyer orgnameInstituto Estadual do Cérebro Paulo Niemeyer orgdiv1Unidade de Neuroendocrinologia Rio de Janeiro RJ Brasil originalUnidade de Neuroendocrinologia, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, RJ, Brasil
                [12 ] normalizedUniversidade Estadual de Campinas orgnameUniversidade Estadual de Campinas orgdiv1Faculdade de Ciências Médicas orgdiv2Departamento de Clínica Médica Campinas SP Brasil originalDepartamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (FCM/Unicamp), Campinas, SP, Brasil
                [13 ] normalizedUniversidade Federal do Ceará orgnameUniversidade Federal do Ceará orgdiv1Hospital Universitário Walter Cantídio orgdiv2Serviço de Endocrinologia Fortaleza CE Brasil originalServiço de Endocrinologia, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFCE), Fortaleza, CE, Brasil
                [14 ] orgnameSanta Casa de Belo Horizonte orgdiv1Serviço de Endocrinologia e Metabologia Belo Horizonte MG Brasil originalServiço de Endocrinologia e Metabologia, Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brasil
                [15 ] normalizedUniversidade Federal de Minas Gerais orgnameUniversidade Federal de Minas Gerais orgdiv1Hospital das Clínicas orgdiv2Serviço de Endocrinologia Belo Horizonte MG Brasil originalServiço de Endocrinologia, Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brasil
                Author notes
                Correspondence to: Lucio Vilar, Hospital das Clínicas, Departamento de Medicina Clínica Av. Prof. Moraes Rego, 1235, Cidade Universitária 50670-901 – Recife, PE, Brasil lvilarf@ 123456gmail.com

                Disclosure: no potential conflict of interest relevant to this article was reported.

                Article
                2359-3997000000032
                10.20945/2359-3997000000032
                10118988
                29768629
                56dd4869-f52a-4092-8e71-42cb41c6f71f

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 03 February 2017
                : 09 August 2017
                Page count
                Figures: 8, Tables: 5, Equations: 0, References: 240
                Categories
                Review

                hyperprolactinemia,prolactinomas,pseudoprolactinomas,macroprolactin,hook-effect,dopamine agonists,pituitary surgery,temozolomide

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