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.

Is IGSF1 involved in human pituitary tumor formation?

IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation.

Clinical and molecular genetics of the phosphodiesterases (PDEs).

Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.

Cyclic AMP and c-KIT signaling in familial testicular germ cell tumor predisposition.

BACKGROUND: Familial testicular germ cell tumors (FTGCTs) are hypothesized to result from the combined interaction of multiple low-penetrance genes. We reported inactivating germline mutations of the cAMP-binding phosphodiesterase 11A (PDE11A) as modifiers of FTGCT risk. Recent genome-wide association studies have identified single-nucleotide polymorphisms in the KITLG gene, the ligand for the cKIT tyrosine kinase receptor, as strong modifiers of susceptibility to both familial and sporadic testicular germ cell tumors. DESIGN: We studied 94 patients with FTGCTs and 50 at-risk male relatives from 63 unrelated kindreds, in whom the PDE11A gene had been sequenced by investigating the association between KITLG genome-wide association study single-nucleotide polymorphisms rs3782179 and rs4474514 and FTGCT risk in these patients and in 692 controls. We also examined cAMP and c-KIT signaling in testicular tissues and cell lines and extended the studies to 2 sporadic cases, one with a PDE11A defect and one without, as a comparison. RESULTS: We found a higher frequency of the KITLG risk alleles in FTGCT patients who also had a PDE11A sequence variant, compared with those with a wild-type PDE11A sequence. In NTERA-2 and Tcam-2 cells transfected with the mutated forms of PDE11A (R52T, F258Y, Y727C, R804H, V820M, R867G, and M878V), cAMP levels were significantly higher, and the relative phosphodiesterase activity was lower than in the wild-type cells. KITLG expression was consistently increased in the presence of PDE11A-inactivating defects, both at the RNA and protein levels, in familial testicular germ cell tumors. The 2 sporadic cases that were studied, one with a PDE11A defect and another without, agreed with the data in FTGTCT and in the cell lines. CONCLUSIONS: Patients with FTGCT and PDE11A defects also carry KITLG risk alleles more frequently. There may be an interaction between cAMP and c-KIT signaling in predisposition to testicular germ cell tumors.

Short-term treatment with cabergoline can lead to tumor shrinkage in patients with nonfunctioning pituitary adenomas.

This study was carried out to evaluate the effectiveness of cabergoline in the treatment of nonfunctioning pituitary adenomas (NFPA), in a short-term follow-up period. Nineteen patients (10 men and 9 women) followed at the University Hospital of Brasilia and harboring nonfunctioning pituitary macroadenomas were enrolled in the study. Eleven patients were previously submitted to transsphenoidal surgery, and in 8 patients no previous treatment had been instituted. Their response to the use of cabergoline (2 mg/week) by 6 months was evaluated. Significant tumor shrinkage (above 25 % from baseline tumor volume) was observed in 6 (31.6 %) of the 19 patients, and no adverse effects were observed during treatment. In 9 patients (47.4 %), a reduction in tumor volume of at least 10 % was noted, whereas tumor growth was observed in four patients (increase above 25 % was only observed in one patient). Cabergoline (2 mg/week) can lead to significant tumor shrinkage in NFPA in a considerable number of patients, and this effect can be observed early (6 months after starting medication). Thus, this therapeutic strategy may be a low cost and safe alternative for treatment of NFPA in patients with remnant or recurrent tumor after transsphenoidal surgery or in those not operated by contraindications or refusal to surgical procedure.

Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations.

CONTEXT: The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas. OBJECTIVE AND DESIGN: The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings. RESULTS: MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions. CONCLUSION: WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others.

Unique gene expression profile associated with an early-onset multiple endocrine neoplasia (MEN1)-associated pituitary adenoma.

CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is caused by mutations in the menin (MEN1) gene. The mechanism(s) by which MEN1 mutations lead to pituitary tumor formation remain(s) unknown. OBJECTIVE: The aim of the study was to identify the pediatric MEN1-associated pituitary tumor transcriptome. PATIENTS AND METHODS: A patient harboring a MEN1 mutation (c.525C>G; p.H139D) who presented with an early-onset mammosomatotroph pituitary adenoma was studied. Microarray analysis was performed in the tumor sample and compared with the profile observed in normal pituitaries and in a sporadic mammosomatotropinoma. Validation of the microarray results was performed using quantitative real-time PCR and immunohistochemical analysis for selected genes. RESULTS: In the MEN1-associated pituitary adenoma, 59 and 24 genes were found to be significantly up- and down-regulated, respectively. The up-regulated genes included those involved in cell growth and maintenance, apoptosis, growth arrest, and tumorigenesis. Moreover, we observed decreased expression in genes neuroendocrine in nature and related to growth or apoptosis. Only 21 of the 59 genes differentially expressed in the MEN1-associated adenoma showed a similar expression profile to that seen in the sporadic mammosomatotropinoma; for some genes an opposite expression profile was observed. CONCLUSIONS: We identified changes in the transcriptome that occur in pituitary GH- and PRL-producing cells after the loss of menin expression; some of the gene changes are necessary for tumor evolution, and others may be tertiary. Nevertheless, the rare overlap between the expression profiles of the MEN1 tumor vs. that of its sporadic counterpart suggests that these tumors evolve along different molecular pathways.

The transcriptome that mediates increased cyclic adenosine monophosphate signaling in PRKAR1A defects and other settings.

OBJECTIVE: To review current knowledge on the involvement of cyclic adenosine monophosphate (cAMP) and interacting signaling pathways in predisposition to tumor formation in primary pigmented nodular adrenocortical disease (PPNAD), a type of bilateral adrenal hyperplasia (BAH) related to the multiple endocrine neoplasia Carney complex, and also in isolated PPNAD and other BAHs. METHODS: We review the pertinent literature and discuss genetic defects associated with various endocrine and nonendocrine tumors. RESULTS: A decade ago, we discovered that PPNAD and the Carney complex are caused by PRKAR1A mutations. PRKAR1A encodes the protein kinase A (PKA) regulatory subunit type IA, an important regulator of cAMP signaling in most cells. Recently, we described PKA or PRKAR1A abnormalities in a variety of other BAHs; in some of these cases, mutations in additional genes of the cAMP signaling pathway, the phosphodiesterases, were identified. Transcriptomic analyses of human lesions or animal models showed that abnormal cAMP/PKA signaling in the adrenal glands, and also in other tissues such as bone, leads to proliferation of tissue-specific pluripotential cells through activation of Wnt signaling. CONCLUSION: Recent findings indicate the relevance of cAMP signaling in the pathogenesis of adrenocortical disease and point to the Wnt signaling pathway as a potential important mediator of tumorigenesis related to increased cAMP or PKA signaling (or both).

Treatment of severe trigeminal headache in patients with pituitary adenomas.

BACKGROUND: The incidence of headache in patients with pituitary adenomas is high, and the underlying pathological mechanisms are not completely understood. OBJECTIVE: We tested the efficacy of percutaneous ganglion block and trigeminal rhizotomy in the treatment of severe trigeminal/autonomic headache associated with pituitary tumors. METHODS: Eleven patients treated surgically for pituitary adenomas in whom intractable trigeminal headaches developed were enrolled in the study and underwent ictal cerebral single-photon emission computed tomography before starting treatment. Initially, all patients underwent a 6-month medical treatment trial. Patients who did not experience improvement in headache severity, addressed by the Headache Impact Test-6 scale, underwent trigeminal percutaneous ganglion blockade. Two patients subsequently underwent trigeminal balloon rhizotomy. RESULTS: Among the 11 patients, 6 did not have improved Headache Impact Test-6 scale scores after 6 months of treatment with medications and underwent trigeminal ganglion blockade. Significant improvement in headache severity was noted in 3 of them. Long-term response was obtained in 1 patient, and the other 2, in whom the response was transient, were then successfully treated with trigeminal rhizotomy. Cerebral single-photon emission computed tomography showed increased uptake in the thalamus/hypothalamus region in patients who responded well to manipulation of the trigeminal-hypothalamic system. CONCLUSION: Percutaneous ganglion blockade and trigeminal rhizotomy may be promising alternative options for the treatment of severe headache in selected patients with pituitary adenomas.

Role of the addition of cabergoline to the management of acromegalic patients resistant to longterm treatment with octreotide LAR.

The aim of this prospective open trial was to evaluate the efficacy in normalizing IGF-I levels of the addition of cabergoline to the treatment of acromegalic patients partially responsive to Octreotide-LAR (OCT-LAR), a long acting somatotastin analog (SSA). Fifty-two patients who did not achieve hormonal control after longterm therapy (at least, 12 months) with OCT-LAR (30 mg every 28 days intramuscularly) were given cabergoline in addition to the SSA treatment. Normalization of IGF-I levels was achieved in 40.4% of patients by 6 months after the addition of cabergoline (1.0-3.0 mg/week; mean, 2.19 ± 0.64), and these patients were considered responsive. Compared to non-responsive subjects, responsive patients had significantly lower mean %ULNR-IGF-I and GH levels. However, the rate of hyperprolactinemia and positive immunohistochemical staining for PRL was similar in both groups, before the addition of cabergoline. Responsive patients were followed for at least 12 months on combination treatment and persisted with normal IGF-I levels. Patients with baseline %ULNR IGF-I up to 220% and/or GH up to 5 ng/ml were those who benefited the most from combination treatment. No patients with %ULNR-IGF-I>250% reached normalization of IGF-I levels. Our findings demonstrated that the addition of cabergoline, even at relatively low doses, is effective in both short- and long-term control of IGF-I levels in acromegalic patients partially responsive to octreotide LAR, particularly in those with mild/moderately elevated GH/IGF-levels, irrespective of prolactin status.

The brazilian version of the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA): Four-stage translation and validation / Versão brasileira do questionário "Quality of Life - Assessment of Growth Hormone Deficiency in Adults" (QoL-AGHDA): Tradução e validação em quatro estágios

OBJECTIVE: This study reports on the Brazilian Portuguese adaptation of the QoL-AGHDA (Quality of Life Assessment of Growth Hormone Deficiency in Adults) for use in adult growth hormone deficient (GHD) patients. MATERIALS AND METHODS: The translation process adopted the dual panel methodology. The questionnaire was tested through field-test interviews (16 GHD patients). In the final stage, data from 120 GHD patients (81 included in a test-retest analysis) were analyzed for internal consistency, test-retest reliability, convergent validity and validity among known groups. RESULTS: The translation panels were successful and the draft version was amended to improve the wording as a result of the field-test interviews. Cronbach's alpha was 0.90 and test-retest reliability 0.88. QoL-AGHDA scores had the expected pattern of association with NHP scale scores and QoL-AGHDA was able to differentiate significantly between patients based on patient-reported general health (p < 0.01) and QoL (p < 0.01). CONCLUSIONS: The adaptation of the QoL-AGHDA for a Brazilian population was successful and the adapted questionnaire was shown to be reliable and valid.

OBJETIVO: Este estudo relata o processo de adaptação da versão brasileira do questionário QoL-AGHDA (Quality of Life - Assessment of Growth Hormone Deficiency in Adults) para pacientes com deficiência do hormônio de crescimento (DGH). MATERIAIS E MÉTODOS: A tradução adotou a metodologia de duplo painel. O questionário foi testado por intermédio de entrevistas direcionadas com 16 pacientes com DGH. No estágio final, dados de 120 pacientes com DGH (81 com teste/reteste) foram analisados para consistência interna, confiabilidade teste/reteste, validade convergente e validade entre grupos conhecidos. RESULTADOS: Os grupos de tradução foram bem-sucedidos e a versão final foi adaptada seguindo sugestões obtidas das entrevistas com os 16 pacientes. O coeficiente alfa de Cronbach foi 0,90, confiabilidade teste/reteste 0,88, escores QoL-AGHDA se correlacionaram com o NHP (p < 0,01) e também com a saúde geral relatada pelos pacientes (p < 0,01). CONCLUSÕES: A adaptação do QoL-AGHDA para a população brasileira foi bem-sucedida, e a nova versão demonstrou ser válida e confiável.

An unusual presentation of pediatric Cushing disease: recurrent corticotropinoma of the posterior pituitary lobe.

Cushing's syndrome (CS) is rare in childhood and adolescence and its diagnosis and work up are often challenging. We report the case of a 15-year-old girl with a recurrent corticotrophin (ACTH)-secreting adenoma, located in the posterior lobe of the pituitary gland. At the age of 11, she presented with classic CS symptoms; biochemical investigation was compatible with ACTH-dependent Cushing disease, although pituitary gland imaging did not show any tumor. Following transsphenoidal surgery (TSS), histopathological analysis identified an ACTH-secreting pituitary microadenoma arising from the posterior gland. The patient went into remission but 4 years later she presented with recurrent CS; this time, pituitary gland imaging showed a microadenoma located in the posterior lobe, which was resected after TSS. Posterior lobe pituitary adenomas are very rare and often hard to diagnose and treat; this is the first case of such a tumor causing recurrent Cushing's disease in a child.

The brazilian version of the Quality of Life Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA): Four-stage translation and validation.

OBJECTIVE: This study reports on the Brazilian Portuguese adaptation of the QoL-AGHDA (Quality of Life Assessment of Growth Hormone Deficiency in Adults) for use in adult growth hormone deficient (GHD) patients. MATERIALS AND METHODS: The translation process adopted the dual panel methodology. The questionnaire was tested through field-test interviews (16 GHD patients). In the final stage, data from 120 GHD patients (81 included in a test-retest analysis) were analyzed for internal consistency, test-retest reliability, convergent validity and validity among known groups. RESULTS: The translation panels were successful and the draft version was amended to improve the wording as a result of the field-test interviews. Cronbach's alpha was 0.90 and test-retest reliability 0.88. QoL-AGHDA scores had the expected pattern of association with NHP scale scores and QoL-AGHDA was able to differentiate significantly between patients based on patient-reported general health (p < 0.01) and QoL (p < 0.01). CONCLUSIONS: The adaptation of the QoL-AGHDA for a Brazilian population was successful and the adapted questionnaire was shown to be reliable and valid.

Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing's disease.

The expression of dopamine receptor subtypes has been reported in corticotroph adenomas, and this finding support the possibility for medical treatment of Cushing's disease (CD) with dopamine agonists when conventional treatment has failed. The aim of this study was to evaluate the effectiveness of cabergoline (at doses of up 3 mg/week), alone or combined with relatively low doses of ketoconazole (up to 400 mg/day), in 12 patients with CD unsuccessfully treated by transsphenoidal surgery. After 6 months of cabergoline therapy, normalization of 24 h urinary free cortisol (UFC) levels occurred in three patients (25%) at doses ranging from 2-3 mg/week, whereas reductions ranging from 15.0 to 48.4% were found in the remaining. The addition of ketonocazole to the nine patients without an adequate response to cabergoline was able to normalize UFC excretion in six patients (66.7%) at doses of 200 mg/day (three patients), 300 mg/day (two patients) and 400 mg/day (one patient). In the remaining patients UFC levels did not normalize but a significant reduction ranging from to 44.4 to 51.7% was achieved. In two of the six responsive patients to combination therapy, the weekly dose of cabergoline could be later reduced from 3 to 2 mg. Our findings demonstrated that cabergoline monotherapy was able to reverse hypercortisolism in 25% of patients with CD unsuccessfully treated by surgery. Moreover, the addition of relatively low doses of ketoconazole led to normalization of UFC in about two-thirds of patients not achieving a full response to cabergoline.

Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene.

BACKGROUND: Germline aryl hydrocarbon receptor-interacting protein (AIP) mutations occur in 15% of familial isolated pituitary adenoma (FIPA) cases. To date, studies have focused on the identification of such mutations in large international cohorts. Detailed genetic and clinical studies within AIP mutation-positive families have been limited. AIM: To undertake a comprehensive study of a large Brazilian FIPA kindred with an E174 frameshift (E174fs) AIP mutation to assess clinical, hormonal, and radiological features in mutation carriers. METHODS: The kindred included 122 subjects across six generations; all underwent clinical examination. Genetic studies were performed to identify E174fs mutation carriers. E174fs-positive subjects underwent magnetic resonance imaging (MRI) and hormonal assessments. RESULTS: Of the ten germline AIP mutation carriers, three had pituitary tumors, while seven were asymptomatic carriers. Three patients with pituitary tumors showed variability in terms of tumor phenotype (two with acromegaly, one with prolactinoma, or mixed prolactin/GH-secreting tumor) and age at diagnosis; both patients with acromegaly had poor responses to octreotide. Tumor AIP immunohistochemistry from the operated patient showed decreased expression when compared with normal tissue. Two adult subjects with normal MRI had elevated IGF-I in the absence of other causes. A 2-year-old child with the E174fs mutation and a normal MRI had premature thelarche, ovarian development, and advanced bone age in the absence of other underlying causes. CONCLUSIONS: The penetrance of pituitary tumors in AIP mutation-positive adult subjects was 33.3%, while clinical/hormonal features were variable. The features noted in AIP-mutation carriers in this kindred suggest that clinical characteristics of such carriers may extend beyond pituitary tumors.

[Endogenous Cushing's syndrome: clinical and laboratorial features in 73 cases]. / Síndrome de Cushing endógena: características clínico-laboratoriais em 73 casos.

We studied clinical and laboratorial features of 73 patients with endogenous Cushing's syndrome, subdivided as follows: 46 (63%) with Cushing's disease (CD), 21 (28.7%) with an adrenal tumor and 6 (8.2%) with ectopic ACTH secretion (EAS). The rate of typical manifestations of hypercortisolism was similar regardless its etiology. In 100% of cases of Cushing's syndrome we observed serum cortisol levels greater than 1.8 microg/dL in low-dose dexamethasone (DMS) suppression tests, as well as elevation of serum or salivary midnight cortisol. However, urinary free cortisol was normal in 11.5% of patients. ACTH levels were suppressed in patients with adrenal tumors, normal or high in CD and always high in EAS. In the 8-mg overnight DMS suppression test, serum cortisol suppression > 50% was observed in 78.2% of cases of CD and in 33.3% of subjects with EAS, while an 80% suppression was only seen in CD. After stimulation with CRH or DDAVP an ACTH increase > 35% occurred in 81% of individuals with CD and 16.6% of those with EAS, while an ACTH increase > 50 achieved 100% specificity. Moreover, the combination of serum cortisol suppression > 50% and an ACTH increase > 35% in both tests only occurred in Cushing's disease. Pituitary magnetic resonance imaging identified 100% of macroadenomas and 59.4% of microadenomas in patients with CD. Among 10 patients that underwent bilateral inferior petrosal sinus sampling, a central-to-peripheral ACTH gradient > 3 after CRH or DDAVP had 90% sensitivity and 100% specificity for Cushing's disease.

Síndrome de cushing endógena: características clínico-laboratoriais em 73 casos / Endogenous cushings syndrome: clinical and laboratorial features in 73 cases

Avaliamos as características clínico-laboratoriais de 73 pacientes com síndrome de Cushing (SC) endógena, assim distribuídos: 46 (63 por cento) com doença de Cushing (DC), 21 (28,7 por cento) com tumores adrenais (TA) e 6 (8,2 por cento) com a síndrome do ACTH ectópico (SAE). A freqüência de manifestações clássicas do hipercortisolismo foi similar, independentemente da etiologia da SC. Em 100 por cento dos casos de SC, observaram-se níveis do cortisol sérico (CS) > 1,8 µg/dL após supressão com doses baixas de dexametasona (DMS), além de elevação do cortisol à meia-noite (sérico ou salivar). Contudo, o cortisol livre urinário foi normal em 11,5 por cento dos pacientes. Os níveis de ACTH mostraram-se suprimidos nos pacientes com TA, normais ou elevados na DC e sempre elevados na SAE. No teste de supressão noturna com 8 mg de DMS, supressão do CS > 50 por cento foi observada em 78,2 por cento dos casos de DC e 33,3 por cento dos casos de SAE, enquanto uma supressão > 80 por cento foi exclusiva da DC. Após estímulo com CRH ou DDAVP, um incremento do ACTH > 35 por cento aconteceu em 81 por cento dos indivíduos com DC e em 16,6 por cento daqueles com SAE, ao passo que um incremento do ACTH > 50 por cento restringiu-se à DC. A combinação de incremento do ACTH > 35 e supressão do CS > 50 por cento foi também exclusiva da DC. A ressonância magnética visualizou 100 por cento dos macroadenomas e 59,4 por cento dos microadenomas hipofisários nos casos de DC. Em 10 pacientes submetidos ao cateterismo bilateral do seio petroso inferior, um gradiente centro-periferia de ACTH > 3 pós-CRH ou DDAVP teve sensibilidade de 90 por cento e especificidade de 100 por cento para a doença de Cushing.

We studied clinical and laboratorial features of 73 patients with endogenous Cushings syndrome, subdivided as follows: 46 (63 percent) with Cushings disease (CD), 21 (28.7 percent) with an adrenal tumor and 6 (8.2 percent) with ectopic ACTH secretion (EAS). The rate of typical manifestations of hypercortisolism was similar regardless its etiology. In 100 percent of cases of Cushings syndrome we observed serum cortisol levels greater than 1.8 µg/dL in low-dose dexamethasone (DMS) suppression tests, as well as elevation of serum or salivary midnight cortisol. However, urinary free cortisol was normal in 11.5 percent of patients. ACTH levels were suppressed in patients with adrenal tumors, normal or high in CD and always high in EAS. In the 8-mg overnight DMS suppression test, serum cortisol suppression > 50 percent was observed in 78.2 percent of cases of CD and in 33.3 percent of subjects with EAS, while an 80 percent suppression was only seen in CD. After stimulation with CRH or DDAVP an ACTH increase > 35 percent occurred in 81 percent of individuals with CD and 16.6 percent of those with EAS, while an ACTH increase > 50 achieved 100 percent specificity. Moreover, the combination of serum cortisol suppression > 50 percent and an ACTH increase > 35 percent in both tests only occurred in Cushings disease. Pituitary magnetic resonance imaging identified 100 percent of macroadenomas and 59.4 percent of microadenomas in patients with CD. Among 10 patients that underwent bilateral inferior petrosal sinus sampling, a central-to-peripheral ACTH gradient > 3 after CRH or DDAVP had 90 percent sensitivity and 100 percent specificity for Cushings disease.