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

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.

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

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.

Mixed germ cell tumor of the pituitary-hypothalamic region presenting as craniopharyngioma: case report and review of the literature / Tumor misto de células germinativas da região hipotálamo-hipofisária apresentando-se como craniofaringioma: relato de caso e revisão da literatura

Craniopharyngiomas and germ cell tumors (GCT) may affect the pituitary-hypothalamic region during childhood. Although different in origin, their clinical and radiological features may be similar. In this article we present a 5-year-old girl with clinical and radiological findings (computer tomography calcification) that were initially considered as craniopharyngioma. However clinical outcome, blood and cerebral spinal fluid tumoral markers, and results from anatomopathology and immunohistochemistry disclosed a mixed GCT. This case report highlights that some clinical features and radiological findings of pituitary-hypothalamic tumors may be misdiagnosed as craniopharyngioma mainly when there is a mature teratoma with cartilaginous tissue differentiation.

Craniofaringiomas e tumores mistos de células germinativas (TCG) podem acometer a região hipotálamo-hipofisária durante a infância. Embora tenham diferentes origens, as manifestações clínicas e achados radiológicos podem ser semelhantes. Nosso objetivo é relatar o caso de uma paciente de 5 anos de idade, cujas manifestações clínicas e achados radiológicos (presença de calcificações à tomografia computadorizada [TC]) foram inicialmente considerados como provável craniofaringioma. No entanto, a piora clínica progressiva, marcadores tumorais séricos e liquóricos elevados, assim como os resultados do estudo anatomopatológico e imunoistoquímico revelaram tratar-se de TCG. Este caso enfatiza que alguns achados clínicos e radiológicos de tumores da região hipotálamo-hipofisária podem ser erroneamente diagnosticados como craniofaringiomas, principalmente se houver presença de teratoma maduro com diferenciação em tecido cartilaginoso.

Mixed germ cell tumor of the pituitary-hypothalamic region presenting as craniopharyngioma: case report and review of the literature.

Craniopharyngiomas and germ cell tumors (GCT) may affect the pituitary-hypothalamic region during childhood. Although different in origin, their clinical and radiological features may be similar. In this article we present a 5-year-old girl with clinical and radiological findings (computer tomography calcification) that were initially considered as craniopharyngioma. However clinical outcome, blood and cerebral spinal fluid tumoral markers, and results from anatomopathology and immunohistochemistry disclosed a mixed GCT. This case report highlights that some clinical features and radiological findings of pituitary-hypothalamic tumors may be misdiagnosed as craniopharyngioma mainly when there is a mature teratoma with cartilaginous tissue differentiation.

Novel MEN1 germline mutations in Brazilian families with multiple endocrine neoplasia type 1.

OBJECTIVE: To characterize clinical features and identify MEN1 germline mutations in Brazilian families with multiple endocrine neoplasia type 1 (MEN1). Settings Non-profit academic centre. PATIENTS: Fourteen Brazilian families with MEN1 and 141 at-risk relatives. RESULTS: We identified 12 different MEN1 disease-causing mutations, seven of them previously unreported: 308delC; 375del21; 549A>T (I147F); 1243delA; 1348T>G (L413R); 1351T>C (L414P) and 1523G>T (W471C). Families with the recurrent mutations 360delTCTA and L413R were shown to be unrelated by mitochondrial-DNA and Y-chromosome haplotype analyses. Most of the MEN1 single point mutations involved evolutionarily conserved residues, whereas most of the deletion/frameshift changes occurred in GC-rich repetitive regions. Genetic screening of 141 at-risk family members identified 38 MEN1 mutation carriers, 37 (97.4%) of whom had at least one major MEN1-related tumour upon clinical investigation. CONCLUSIONS: High frequencies of MEN1 gene mutations were detected in Brazilian families with MEN1, including seven new genetic mutations that are predicted to cause inactivation of the MEN1 tumour suppressor gene. Our data underscore the need to implement a systematic MEN1 screening programme in Brazil.

Germline mutation in the aryl hydrocarbon receptor interacting protein gene in familial somatotropinoma.

CONTEXT: Acromegaly is usually sporadic, but familial cases occur in association with several familial pituitary tumor syndromes. Recently mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were associated with familial pituitary adenoma predisposition. OBJECTIVE: The objective of the study was to investigate the status of AIP in a pituitary tumor predisposition family. SETTINGS: The study was conducted at a nonprofit academic center and medical centers. PATIENTS: Eighteen members of a Brazilian family with acromegaly were studied. RESULTS: A novel germline mutation in the AIP gene, Y268X, predicted to generate a protein lacking two conserved domains, was identified in four members of this family: two siblings with early-onset acromegaly; a third, 41-yr-old sibling with a microadenoma but no clinical features of disease, and his 3-yr-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls. CONCLUSIONS: We confirm the role of the AIP gene in familial acromegaly. This finding increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. Establishment of genotype-phenotype correlations in AIP mutant tumors will determine whether AIP screening can be used as a tool for clinical surveillance and genetic counseling of families with pituitary tumor predisposition. The underlying basis for the phenotypic variation within AIP-mutant families and the mechanism of AIP-mediated tumorigenesis remain to be defined.

Macroprolactinomas masquerading as pseudoprolactinomas: the high dose hook effect

Serum prolactin level is very important to discriminate prolactiomas from other causes of hyperprolactinemia, specially pseudoprolactinomas. We describe two hyperprolactinemic men: case 1 is 28y old with headache, left eye visual loss and ptosis associated with a huge mass of the sellar region who was operated on elsewhere by transcranial route. These was no visual amelioration. Two months after surgery the patient was admitted to our Unit with impairment of right eye vision. Galactorrhea was found and imaging evaluation showed persistence of a large tumor. After blood sampling for hormonal assessment, oral bromocriptine (10 mg/day) was started and a dramatic right visual improvement was noticed. However, basal prolactin by immunoradiometric assay (IRMA) was 97mug/L. Due to the clinical signs and response suggesting prolactinoma, prolactin level was reassessed. A two-incubation and serial dilution of the same sample up to 1:1,200 disclosed a prolactin value of 25,572 mug/L. Case 2 is 20y old with headache, bitemporal hemianopsia, seizures and hypogonadism secondary to a giant tumor arising from the sellas region. Initial serum prolactin level measured by IRMA was 104 mug/L, which after two-incubations and dilutions up to 1:200 disclosed a value of 17,736 mug/L; clinical treatment was instituted with good results. In order to avoid unnecessary surgeries, we recommend a two-incubation procedure in routine prolactin determinations when IRMA is used.