Evaluation of the DDAVP test in the diagnosis of Cushing's Disease.

OBJECTIVE: To analyse the performance of the desmopressin (DDAVP) test in the diagnosis of Cushing's disease (CD). METHODS: This was a prospective cohort study of 124 patients with suspected hypercortisolism who were recruited from an outpatient endocrinology clinic and investigated for Cushing's syndrome (CS). The ACTH and cortisol responses to the DDAVP test were assessed to determine patient diagnosis and test the procedure's diagnostic accuracy. RESULTS: A total of 68 patients had CD, while 56 had suspected CS. According to ROC analysis, an ACTH peak of 71·8 pg/ml (15·8 pmol/l) following DDAVP administration was able to diagnose CD with a specificity of 94·6% and a sensitivity of 90·8%, a negative predictive value (NPV) of 89·9% and a positive predictive value (PPV) of 95·3%. An absolute ACTH increment ≥37 pg/ml (8·1 pmol/l) over baseline had a sensitivity of 88·0%, specificity of 96·4%, NPV of 87·0% and PPV of 95·3% in diagnosing CD. Only 2 of 56 cases without CD had an absolute ACTH increment ≥37 pg/ml (8·1 pmol/l) over baseline. The DDAVP test was superior to other clinical instruments in diagnosing CS. CONCLUSIONS: The DDAVP test could be a useful additional tool to diagnose CD in patients with suspected CS.

Evaluation of Cushing's disease remission after transsphenoidal surgery based on early serum cortisol dynamics.

OBJECTIVE: To evaluate the ability of post-transsphenoidal pituitary surgery (TSS) serum cortisol levels (s-cortisol) to predict surgical remission and recurrence of Cushing's disease (CD). DESIGN: One hundred and three patients with CD from a tertiary referral centre were prospectively analysed over 6·0 ± 4·8 years of follow-up. Twenty patients received perioperative glucocorticoids as routine care and had s-cortisol measured 10-12 days after TSS (Protocol I). Eighty-six patients (91 surgeries) had s-cortisol measured at 6, 12, 18, 24, 48 h, and 10-12 days after TSS, and received glucocorticoids only in case of adrenal insufficiency (Protocol II). MAIN OUTCOMES: Remission [clinical signs and symptoms of adrenal insufficiency (or hypocortisolism) plus cortisol <3 µg/dl on the 1-mg overnight test (OT) and/or normal free urinary cortisol] during follow-up. Recurrence was defined as loss of remission criteria at least 1 year after TSS. RESULTS: The remission rate after first TSS was 80%; 8% had recurrence. An s-cortisol nadir ≤3·5 µg/dl within 48 h after TSS had sensitivity of 73%, specificity and positive predictive value (PPV) of 100% and negative predictive value (NPV) of 60% and an s-cortisol nadir ≤5·7 µg/dl within 10-12 days of TSS had specificity and PPV of 100% and sensitivity of 91% NPV of 78% for CD remission. CONCLUSION: At hospital discharge, the s-cortisol nadir within 48 h after TSS was already able to predict surgical remission for some patients, and the s-cortisol nadir within 10-12 days of TSS was able to predict cohort-wide surgical remission.

[Assessment of the hypothalamic-pituitary-adrenal axis in Cushing's disease diagnosis and remission]. / Avaliação do eixo hipotálamo-hipófise adrenal no diagnóstico e na remissão da doença de Cushing.

Cushing's disease (CD) remains a medical challenge, with many questions still unanswered. Successful treatment of CD patients is closely related to correct approach to syndromic and etiological diagnosis, besides the experience and talent of the neurosurgeon. Pituitary transsphenoidal adenomectomy is the treatment of choice for DC. Assessment of remission after surgery and recurrence in the long term is an even greater challenge. In this regard, special attention should be paid to the role of postoperative serum cortisol as a marker of CD remission. Additionally, the postoperative use of exogenous glucocorticoids only in cases of adrenal insufficiency has been suggested by some authors as an essential practice to enable the use of serum cortisol in this scenario. In this article, we review the forms of evaluation of DC activity, and markers of remission and relapse of CD after transsphenoidal surgery.

Avaliação do eixo hipotálamo-hipófise adrenal no diagnóstico e na remissão da doença de Cushing / Assessment of the hypothalamic-pituitary-adrenal axis in Cushing's disease diagnosis and remission

A doença de Cushing (DC) permanece um desafio médico com muitas questões ainda não respondidas. O sucesso terapêutico dos pacientes com DC está ligado à correta investigação do diagnóstico síndrômico e etiológico, além da experiência e talento do neurocirurgião. A adenomectomia hipofisária transesfenoidal constitui-se no tratamento de escolha para a DC. A avaliação da remissão da doença no pós-operatório e da recorrência em longo prazo constitui um desafio ainda maior. Especial destaque deve ser dado para o cortisol sérico no pós-operatório como marcador de remissão. Adicionalmente, o uso de corticoide exógeno no pós-operatório apenas em vigência de insuficiência adrenal tem sido sugerido por alguns autores como requisito essencial para permitir a correta interpretação do cortisol sérico nesse cenário. Neste artigo, revisamos as formas de avaliação da atividade da DC e os marcadores de remissão e recidiva da DC após a realização da cirurgia transesfenoidal.

Cushing's disease (CD) remains a medical challenge, with many questions still unanswered. Successful treatment of CD patients is closely related to correct approach to syndromic and etiological diagnosis, besides the experience and talent of the neurosurgeon. Pituitary transsphenoidal adenomectomy is the treatment of choice for DC. Assessment of remission after surgery and recurrence in the long term is an even greater challenge. In this regard, special attention should be paid to the role of postoperative serum cortisol as a marker of CD remission. Additionally, the postoperative use of exogenous glucocorticoids only in cases of adrenal insufficiency has been suggested by some authors as an essential practice to enable the use of serum cortisol in this scenario. In this article, we review the forms of evaluation of DC activity, and markers of remission and relapse of CD after transsphenoidal surgery.

Criteria of cure and remission in Cushing's disease: an update: [review]

We review the clinical and biochemical criteria used for evaluation of the transsphenoidal pituitary surgery results in the treatment of Cushing's disease (CD). Firstly, we discuss the pathophysiology of the hypothalamic-pituitary-adrenal axis in normal subjects and patients with CD. Considering the series published in the last 25 years, we observed a significant variation in the remission or cure criteria, including the choice of biochemical tests, timing, threshold values to define remission, and the interference of glucocorticoid replacement or previous treatment. In this context we emphasize serum cortisol levels obtained early (from hours to 12 days) in the postoperative period without any glucocorticoid replacement or treatment. Our experience demonstrates that: (i) early cortisol < 5 to 7 µg/dl, (ii) a period of glucocorticoid dependence > 6 mo, (iii) absence of response of cortisol/ACTH to CRH or DDAVP, (iv) return of dexamethasone suppression, and circadian rhythm of cortisol are appropriate indices of remission of CD. In patients with undetectable cortisol levels early after surgery, recurrence seems to be low. Finally, although certain biochemical patterns are more suggestive of remission or surgical failure, none has been proven to be completely accurate, with recurrence observed in approximately 10 to 15 percent of the patients in long-term follow-up. We recommended that patients with CD should have long-term monitoring of the CRH-ACTH-cortisol axis and associated co-morbidities, especially hypopituitarism, diabetes mellitus, hypertension, cardiovascular disturbances, and osteoporosis.

Neste artigo, são revisados os principais critérios clínicos e hormonais utilizados para avaliação do tratamento cirúrgico da Doença de Cushing (DC). Inicialmente são comentados aspectos fisiopatológicos que orientam a avaliação hormonal e os principais fatores clínicos, laboratoriais, cirúrgicos e histológicos associados com melhores resultados, observados nas principais séries da literatura e em pacientes acompanhados prospectivamente pelos autores. Foram revisados, também, critérios adotados nas principais séries da literatura, nos últimos 25 anos, chamando-se atenção para as dosagens hormonais, o momento em que foram realizadas, a possibilidade de interferência de tratamentos prévios e da reposição glicocorticóide. À seguir, essas dosagens são discutidas salientando-se a importância do cortisol obtido seqüencialmente no pós-operatório e sem a interferência de reposição glicocorticóide. A experiência prospectiva dos autores, recentemente referendada na literatura, demonstra que valores de cortisol < 5 a 7 µg/dl associados com um período de dependência aos glicocorticóides > 6 meses, ausência de resposta do ACTH/cortisol ao DDAVP e/ou CRH, retorno da supressão à dexametasona e do ritmo circadiano, estão associados com remissão da DC. Em pacientes com cortisol indetectável após cirurgia transesfenoidal, a chance de recidiva parece ser menor do que naqueles em que se observa cortisol detectável. Finalmente, chamamos a atenção para que, mesmo adotando critérios rígidos de avaliação, a recidiva da DC pode ocorrer a longo prazo em até 15 por cento dos casos, recomendando-se, portanto, que esses pacientes sejam acompanhados por tempo indeterminado, com monitorização cuidadosa do eixo CRH-ACTH-cortisol e de suas co-morbidades, especialmente hipopituitarismo, diabete melito, hipertensão arterial, alterações cardiovasculares e osteoporose.

Substantial shrinkage of adenomas cosecreting growth hormone and prolactin with use of cabergoline therapy.

OBJECTIVE: To present 2 cases of patients with acromegaly and severe hyperprolactinemia whose primary therapy with cabergoline resulted in hormonal normalization and a considerable reduction in the size of their somatotroph macroadenomas. METHODS: We summarize the clinical presentation and the pertinent laboratory findings in 2 patients with acromegaly, as well as their clinical response to the therapy with cabergoline. A review of the literature regarding the use of cabergoline in acromegaly is also presented. RESULTS: A 48-year-old man (case 1) and a 26-year-old woman (case 2) were found to have acromegaly associated with very high levels of serum prolactin (2,700 and 5,250 ng/mL, respectively). These patients received first line therapy with cabergoline that resulted not only in clinical improvement and normalization of growth hormone, prolactin, and insulin-like growth factor-I levels but also in a substantial reduction in the size of their somatotroph macroadenomas. By 6 months after the patients began to take cabergoline, tumor shrinkage of 94% (in case 1) and of 70% (in case 2) was demonstrated by magnetic resonance imaging. CONCLUSION: Our findings demonstrate that cabergoline should be considered for medical treatment of adenomas cosecreting growth hormone and prolactin, even in the presence of large tumors with appreciable suprasellar extension, because substantial tumor shrinkage is possible with this therapy.

Criteria of cure and remission in Cushing's disease: an update.

We review the clinical and biochemical criteria used for evaluation of the transsphenoidal pituitary surgery results in the treatment of Cushing's disease (CD). Firstly, we discuss the pathophysiology of the hypothalamic-pituitary-adrenal axis in normal subjects and patients with CD. Considering the series published in the last 25 years, we observed a significant variation in the remission or cure criteria, including the choice of biochemical tests, timing, threshold values to define remission, and the interference of glucocorticoid replacement or previous treatment. In this context we emphasize serum cortisol levels obtained early (from hours to 12 days) in the postoperative period without any glucocorticoid replacement or treatment. Our experience demonstrates that: (i) early cortisol < 5 to 7 microg/dl, (ii) a period of glucocorticoid dependence > 6 mo, (iii) absence of response of cortisol/ACTH to CRH or DDAVP, (iv) return of dexamethasone suppression, and circadian rhythm of cortisol are appropriate indices of remission of CD. In patients with undetectable cortisol levels early after surgery, recurrence seems to be low. Finally, although certain biochemical patterns are more suggestive of remission or surgical failure, none has been proven to be completely accurate, with recurrence observed in approximately 10 to 15% of the patients in long-term follow-up. We recommended that patients with CD should have long-term monitoring of the CRH-ACTH-cortisol axis and associated co-morbidities, especially hypopituitarism, diabetes mellitus, hypertension, cardiovascular disturbances, and osteoporosis.

Tumores não hipofisários da região selar / Nonpituitary tumors of the sellar region

A hipófise, a sela túrcica e a região peri-selar podem ser acometidas por uma série de lesões, incluindo tumores benignos e malignos, bem como uma ampla variedade de doenças não neoplásicas. Os aspectos clínicos e radiológicos podem auxiliar no diagnóstico diferencial destas lesões. Porém, em muitos casos, somente a análise histopatológica pode estabelecer o diagnóstico definitivo. Neste artigo, revisamos principais tumores não hipofisários da região selar e peri-selar, ressaltando seus aspectos endócrinos mais relevantes.

Octreotide-LAR + adrenalectomia bilateral no manejo de tumores carcinóides produtores de ACTH / Octreotide + bilateral adrenalectomy in the management of ACTH-producing carcinoid tumors

A síndrome de Cushing (SC) por ACTH ectópico é um distúrbio com alta morbi/mortalidade, cujo manejo necessita de medidas terapêuticas rápidas e eficientes. Os tumores carcinóides produtores de ACTH (TuCA-ACTH) apresentam quadro ainda mais grave em decorrência dos distúrbios associados à síndrome carcinóide (SCA) que acentuam as repercussões do hipercortisolismo. Assim, o manejo de pacientes com TuCA-ACTH deve incluir o controle do hipercortisolismo e do distúrbio carcinóide, sendo escassas informações que abordam tais estratégias. Relatamos 3 pacientes (2F, 1M) com TuCA-ACTH (2 pancreáticos e 1 oculto) que apresentavam manifestações clínicas de SC (n= 3) e SCA (n= 2): 2 foram investigados inicialmente por apresentarem SC e um, SCA. Em todos ocorreu hipocalemia espontânea, hipertensão arterial e diabetes mellitus, sendo demonstrada a presença de hipercortisolismo severo e elevação de ACTH. A administração de octreotide-LAR reduziu os níveis de ACTH de 230.000 para 30.000pg/ml no caso 1, e controlou os sintomas da SCA e das lesões neoplásicas no caso 2, enquanto o octreotide subcutâneo controlou a SCA e reduziu parcialmente os sintomas do hipercortisolismo no caso 3. Os 3 pacientes foram adrenalectomizados bilateralmente, medida essencial para o controle da SC (desaparecimento da hipocalemia, miopatia, hipertensão arterial e diabetes mellitus). Nossos dados demonstram que a associação destas estratégias, em conjunto com terapias anti-neoplásicas, pode contribuir para estabilização e/ou controle definitivo dos TuCA-ACTH.

[Nonpituitary tumors of the sellar region]. / Tumores não hipofisários da região selar.

The pituitary gland, sella turcica and the parasellar region can be involved by a wide variety of lesions, including benign and malignant neoplasms as well as a wide variety of non neoplastic tumor-like lesions. Clinical and radiological aspects could help in the differential diagnosis of these lesions. Nevertheless, in many cases only the histopathological analysis could establish the definitive diagnosis. In this paper, we review the nonpituitary tumors of the sellar region emphasizing the associated hormonal disturbances.

[Octreotide + bilateral adrenalectomy in the management of ACTH-producing carcinoid tumors]. / Octreotide-LAR + adrenalectomia bilateral no manejo de tumores carcinóides produtores de ACTH.

Cushing's syndrome (CS) due to ectopic ACTH secretion has a high morbidity and mortality. Thus, rapid treatment of ectopic CS is mandatory. Carcinoid tumors associated with ectopic ACTH (CTu-ACTH) syndrome represent a more severe clinical picture, due to the carcinoid symptoms that worsen the hypercortisolism state. Management of patients with CTu-ACTH should include the control of hypercortisolism, as well as the carcinoid disturbance. We report 3 patients (2F, 1M) with CTu-ACTH (2 pancreatic, 1 occult) who presented with clinical manifestations of CS (n= 3) and carcinoid syndrome (2): 2 were initially investigated for CS and 1 carcinoid syndrome. In all hypokalemia, hypertension and diabetes mellitus were associated with severe hypercortisolism and high ACTH levels. Administration of octreotide-LAR reduced ACTH levels from 230,000 to 30,000 pg/ml in patient 1, and controlled symptoms of carcinoid syndrome and neoplasic lesions in patient 2; treatment with subcutaneous octreotide in patient 3 controlled carcinoid syndrome and partially reduced symptoms of hypercortisolism. All 3 patients were submitted to bilateral adrenalectomy to control CS. Our data show that combined anti-neoplastic therapy may contribute to the stabilization and/or definitive control of CTu-ACTH.

Síndrome de Cushing: é possível simplificar e padronizar sua abordagem diagnóstica? / Cushing's syndrome: is it possible a standard and simple diagnostic approach?

A síndrome de Cushing representa um desafio diagnóstico, requerendo suspeita clínica apurada, conhecimento adequado da regulaçäo hormonal do eixo hipotálamo-hipófise-adrenal, aplicaçäo precisa de testes funcionais que estimulam ou inibem este eixo e a indicaçäo de exames de imagem resolutivos para as diversas etiologias investigadas. Neste artigo, discutimos a abordagem diagnóstica da síndrome de Cushing, analisando a aplicaçäo dos diversos testes utilizados tanto para o diagnóstico sindrômico como para definiçäo da sua etiologia. Destacamos o diagnóstico diferencial entre a doença de Cushing leve e os estados de pseudo-Cushing e entre doença de Cushing e síndrome do ACTH ectópico. Baseados nestes conceitos e conhecimentos, e em nossa experiência, propomos um modelo de abordagem para pacientes com suspeita de síndrome de Cushing, ressaltando que, em algumas situaçöes, para um correto diagnóstico etiológico, säo necessários métodos invasivos e sofisticados