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.

A review of Cushing's disease treatment by the Department of Neuroendocrinology of the Brazilian Society of Endocrinology and Metabolism.

The treatment objectives for a patient with Cushing's disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails. There are several options of medical treatment, although cabergoline and ketoconazole are the most commonly used alone or in combination. Novel treatments are also addressed in this review. Different therapeutic approaches are frequently needed on an individual basis, both before and, particularly, after surgery, and they should be individualized. The objective of the present review is to provide the necessary information to achieve a more effective treatment for CD. It is recommended that patients with CD be followed at tertiary care centers with experience in treating this condition.

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.

A review of Cushing's disease treatment by the Department of Neuroendocrinology of the Brazilian Society of Endocrinology and Metabolism

ABSTRACT The treatment objectives for a patient with Cushing's disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails. There are several options of medical treatment, although cabergoline and ketoconazole are the most commonly used alone or in combination. Novel treatments are also addressed in this review. Different therapeutic approaches are frequently needed on an individual basis, both before and, particularly, after surgery, and they should be individualized. The objective of the present review is to provide the necessary information to achieve a more effective treatment for CD. It is recommended that patients with CD be followed at tertiary care centers with experience in treating this condition.

Long-Term Remission of Acromegaly after Octreotide Withdrawal Is an Uncommon and Frequently Unsustainable Event.

BACKGROUND: Long-term remission of acromegaly after somatostatin analog withdrawal has been reported in 18-42% of patients in studies with a relatively small number of patients using different inclusion and remission criteria. The objectives of this study were to establish the probability and predictive factors for short- and long-term remission [normal IGF-1 for age/sex: IGF-1 ≤1.00 × upper limit of normal (ULN)] after octreotide long-acting release (LAR) withdrawal in a larger population of well-controlled patients with acromegaly (normal mean IGF-1 in the last 24 months). METHODS: This is a prospective multicenter study in which 58 well-controlled patients with acromegaly receiving only octreotide LAR as a primary or postsurgical treatment were included in 14 university centers in Brazil. All patients had been on stable doses and dose intervals of octreotide LAR in the last year, and none had been submitted to radiotherapy. The main outcome measure was serum IGF-1 after 8 weeks (short-term) and 60 weeks (long-term) of octreotide LAR withdrawal. RESULTS: Seventeen of 58 patients (29%) were in remission in the short term, and only 4 patients achieved long-term remission after treatment withdrawal. The Kaplan-Meier estimated remission probability at 60 weeks was 7% and decreased to 5% at 72 weeks. The short-term remission rate was significantly higher (44%; p = 0.017) in patients with pretreatment IGF-1 <2.4 × ULN. No other predictive factor for short- or long-term remission was found. CONCLUSION: Our results show that long-term remission of acromegaly after octreotide LAR withdrawal was an uncommon and frequently unsustainable event and do not support the recommendation of a systematic withdrawal of treatment in controlled patients.

Recommendations of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism for the diagnosis of Cushing's disease in Brazil.

Although it is a rare condition, the accurate diagnosis and treatment of Cushing's disease is important due to its higher morbidity and mortality compared to the general population, which is attributed to cardiovascular diseases, diabetes mellitus and infections. Screening for hypercortisolism is recommended for patients who present multiple and progressive clinical signs and symptoms, especially those who are considered to be more specific to Cushing's syndrome, abnormal findings relative to age (e.g., spinal osteoporosis and high blood pressure in young patients), weight gain associated with reduced growth rate in the pediatric population and for those with adrenal incidentalomas. Routine screening is not recommended for other groups of patients, such as those with obesity or diabetes mellitus. Magnetic resonance imaging (MRI) of the pituitary, the corticotropin-releasing hormone (CRH) test and the high-dose dexamethasone suppression test are the main tests for the differential diagnosis of ACTH-dependent Cushing's syndrome. Bilateral and simultaneous petrosal sinus sampling is the gold standard method and is performed when the triad of initial tests is inconclusive, doubtful or conflicting. The aim of this article is to provide information on the early detection and establishment of a proper diagnosis of Cushing's disease, recommending follow-up of these patients at experienced referral centers. Arch Endocrinol Metab. 2016;60(3):267-86.

Recommendations of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism for the diagnosis of Cushing's disease in Brazil

ABSTRACT Although it is a rare condition, the accurate diagnosis and treatment of Cushing’s disease is important due to its higher morbidity and mortality compared to the general population, which is attributed to cardiovascular diseases, diabetes mellitus and infections. Screening for hypercortisolism is recommended for patients who present multiple and progressive clinical signs and symptoms, especially those who are considered to be more specific to Cushing’s syndrome, abnormal findings relative to age (e.g., spinal osteoporosis and high blood pressure in young patients), weight gain associated with reduced growth rate in the pediatric population and for those with adrenal incidentalomas. Routine screening is not recommended for other groups of patients, such as those with obesity or diabetes mellitus. Magnetic resonance imaging (MRI) of the pituitary, the corticotropin-releasing hormone (CRH) test and the high-dose dexamethasone suppression test are the main tests for the differential diagnosis of ACTH-dependent Cushing’s syndrome. Bilateral and simultaneous petrosal sinus sampling is the gold standard method and is performed when the triad of initial tests is inconclusive, doubtful or conflicting. The aim of this article is to provide information on the early detection and establishment of a proper diagnosis of Cushing’s disease, recommending follow-up of these patients at experienced referral centers. Arch Endocrinol Metab. 2016;60(3):267-86.

Role of ambulatory blood pressure monitoring in patients with acromegaly.

BACKGROUND: Hypertension is associated with increased cardiovascular deaths in patients with acromegaly. OBJECTIVE: To evaluate the accuracy of blood pressure (BP) by 24-h ambulatory blood pressure monitoring (ABPM) and office BP measurements to represent the real BP status in acromegalic patients and its relationship with acromegalic activity and echocardiogram parameters. PATIENTS AND METHODS: Cohort of 37 patients with acromegaly in a tertiary endocrine outpatient service. RESULTS: Twenty-three percent of the patients were considered hypertensive by ABPM versus 32% by office BP measurements (P = 0.006). BP obtained from the ABPM was associated with growth hormone, insulin-like growth factor type 1 levels and echocardiogram parameters of acromegalic myocardiopathy. Nondipper behavior presented a significant association with the hormonal profile. CONCLUSION: BP levels assessed by ABPM were associated with acromegalic activity and echocardiogram parameters. ABPM can correctly identify BP levels and their repercussion on acromegalic patients.

A successful case of Cushing's disease pregnancy treated with ketoconazole.

PURPOSE: The association of pregnancy and Cushing's disease (CD) is rare. Treatment of Cushing's syndrome (CS) is imperative to reduce maternal and fetal morbidity. Ketoconazole is a widely used drug for CS control when the woman is not pregnant but concerns about its teratogenicity and embryotoxicity restricted its use during pregnancy. METHODS AND RESULTS: We describe a case of a CD patient managed with Ketoconazole during the first and second trimester and other cares for her metabolic CS aspects during pregnancy. She delivered a normal female baby. CONCLUSIONS: It is supposed that even with treatment the relatively hypercortisolemic mother could protect her child from the embryotoxicity of ketoconazole as proved in rat fetuses and we suggest that ketoconazole could be an emergency pharmacological therapeutic option for CS management during pregnancy.

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.

Management of the brain-dead organ donor: a systematic review and meta-analysis.

BACKGROUND: The shortage of organs is a limitation for transplantation, making the care of potential organ donors an important issue. The present systematic review and meta-analysis was carried out to assess the efficacy of interventions to stabilize hemodynamics in brain-dead donors or to improve organ function and outcomes of transplantation. METHODS: Medline, Embase, and Cochrane databases were searched. Of 5096 articles retrieved, 39 randomized controlled trials were selected. Twenty were included in a qualitative synthesis, providing data on 1277 patients. The main interventions described were desmopressin use, triiodothyronine and methylprednisolone replacement, fluid management, vasopressor therapy, mechanical ventilation strategies, and surgical techniques. RESULTS: Three meta-analyses were conducted: the first included two studies and showed that desmopressin administered to brain-dead patients was not advantageous with respect to early organ function in kidney recipients (relative risk, 0.97; 95% confidence interval [CI], 0.85-1.10; I(2) = 0%; P = 0.809). The second included four studies and showed that triiodothyronine did not add hemodynamic benefits versus standard management (weighted mean difference, 0.15; 95% CI, -0.13 to 0.42; I(2) = 17.4%; P = 0.304). The third meta-analysis (two studies) showed that ischemic liver preconditioning during harvesting procedures did not benefit survival (relative risk, 1.0; 95% CI, 0.93-1.08; I(2) = 0%; P = 0.459). CONCLUSION: The present results suggest limited efficacy of interventions focusing on the management of brain-dead donors.

[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.

Comparison of cumulative incidence analysis and Kaplan-Meier for analysis of shock reversal in patients with septic shock.

INTRODUCTION: Kaplan-Meier (KM) has become the most used method to evaluate time-to-event analysis, although it is unsuitable in competing event situations such as death and shock reversal. Despite that the use of this methodology is not widely disseminated, cumulative incidence analysis (CIA) is more appropriate in these situations. We used CIA and KM (with 2 different techniques of censoring) to compare shock reversal in a cohort of patients with septic shock after steroid therapy. Furthermore, we have analyzed shock reversal in responders and nonresponders to high-dose cortrosyn test (250 µg). METHODS: Analysis of shock reversal in a cohort of 74 patients with septic shock at a university hospital was done. RESULTS: Shock reversal by the 28th day was estimated to be 88% and 72% by KM methods and 59% by CIA. In nonresponders to cortrosyn test (Δ ≤ 9 µg/dL), shock reversal was estimated in 80% and 56% according to KM and 47% according to CIA. As for responders to cortrosyn test, shock reversal was estimated in 90% and 77% according to KM and 64% according to the CIA method. CONCLUSION: Kaplan-Meier overestimates shock reversal. Cumulative incidence analysis seems to be a more appropriate method to analyze shock reversal. Future trials intended to analyze shock reversal should apply CIA.

Diagnosis of adrenal failure in critically ill patients.

In the last two decades there was important evolution on the knowledge of the function of the hypothalamic-pituitary-adrenal axis. In the last decade, the expression "relative adrenal insufficiency" (RAI) was created, and more recently "critical illness-related corticosteroid insufficiency" (CIRCI) was used to designate those patients in which cortisol production was not sufficiently increased in stress situations. Patients with CIRCI have elevated hospital morbidity and mortality. Currently, there is a wide discussion about diagnostic criteria for this dysfunction. Besides basal cortisol, some publications now study the role of other tests, such as cortrosyn test - either in low (1 µg) or high doses (250 µg); free cortisol, salivary cortisol, metyrapone test and others. With this review, we aimed at summarizing the results of the most influent papers that intended to define diagnostic criteria for CIRCI. We also suggest an approach for CIRCI diagnosis and make it clear that the decision about steroid therapy in septic shock patients is matter apart from RAI.

Pseudotumor cerebri during Cushing's disease treatment with ketoconazole.

Benign intracranial hypertension (Pseudotumor cerebri) has been described as related to the reduction in steroid levels in Cushing's disease (CD), especially after surgical remission. Ketoconazole is a common and effective adjuvant therapy for hypercortisolism, but the major concern is liver enzyme dysfunction. We describe here the case of a 12-year old girl with CD who developed benign intracranial hypertension during treatment with ketoconazole. She presented headache, vomiting, a black spot on her right temporal visual field, and signs of elevated intracranial pressure. Pituitary image was normal on magnetic resonance image (MRI), and all symptoms improved after treatment with acetazolamide. We call attention to the diagnosis of this disorder in CD patients, especially children on ketoconazole treatment, because it could be confounded with adrenal insufficiency and lead to definitive severe visual impairment.

Pseudotumor cerebri during Cushing's disease treatment with ketoconazole / Pseudotumor cerebral durante o tratamento de doença de Cushing com cetoconazol

Benign intracranial hypertension (Pseudotumor cerebri) has been described as related to the reduction in steroid levels in Cushing's disease (CD), especially after surgical remission. Ketoconazole is a common and effective adjuvant therapy for hypercortisolism, but the major concern is liver enzyme dysfunction. We describe here the case of a 12-year old girl with CD who developed benign intracranial hypertension during treatment with ketoconazole. She presented headache, vomiting, a black spot on her right temporal visual field, and signs of elevated intracranial pressure. Pituitary image was normal on magnetic resonance image (MRI), and all symptoms improved after treatment with acetazolamide. We call attention to the diagnosis of this disorder in CD patients, especially children on ketoconazole treatment, because it could be confounded with adrenal insufficiency and lead to definitive severe visual impairment.

Hipertensão intracraniana benigna (Pseudotumor cerebral) tem sido descrita relacionada à redução dos níveis de esteroides séricos na doença de Cushing (DC), especialmente após a remissão cirúrgica. O cetoconazol é uma opção efetiva e de uso rotineiro como adjuvante na terapêutica do hipercortisolismo, tendo como paraefeito mais temido a toxicidade hepática. Relatamos o caso de uma menina com 12 anos de idade portadora de DC que desenvolveu hipertensão intracraniana benigna durante tratamento com cetoconazol. Apresentou-se com cefaleia, vômitos, comprometimento do campo visual temporal direito e sinais de hipertensão intracraniana. A ressonância magnética (RM) de hipófise era normal e todos os sinais e sintomas resolveram-se com uso de acetazolamida. Chamamos a atenção para esse diagnóstico nos pacientes com DC, especialmente crianças, em tratamento com cetoconazol, porque ele pode ser confundido com insuficiência adrenal e causar comprometimento visual severo e definitivo.

Diagnosis of adrenal failure in critically ill patients / Diagnóstico de insuficiência adrenal em pacientes críticos

In the last two decades there was important evolution on the knowledge of the function of the hypothalamic-pituitary-adrenal axis. In the last decade, the expression "relative adrenal insufficiency" (RAI) was created, and more recently "critical illness-related corticosteroid insufficiency" (CIRCI) was used to designate those patients in which cortisol production was not sufficiently increased in stress situations. Patients with CIRCI have elevated hospital morbidity and mortality. Currently, there is a wide discussion about diagnostic criteria for this dysfunction. Besides basal cortisol, some publications now study the role of other tests, such as cortrosyn test - either in low (1 μg) or high doses (250 μg); free cortisol, salivary cortisol, metyrapone test and others. With this review, we aimed at summarizing the results of the most influent papers that intended to define diagnostic criteria for CIRCI. We also suggest an approach for CIRCI diagnosis and make it clear that the decision about steroid therapy in septic shock patients is matter apart from RAI.

Nas últimas décadas, houve uma importante evolução no conhecimento sobre a função do eixo hipotálamo-pituitária-adrenal. Na última década, foi cunhada a expressão "insuficiência adrenal relativa" (IAR) e, mais recentemente, a expressão "insuficiência adrenal relacionada à doença grave" (CIRCI) foi utilizada para designar aqueles pacientes nos quais a produção de cortisol não era suficientemente elevada em situações de estresse. Pacientes com CIRCI apresentam elevada morbidade e mortalidade em hospitais. Atualmente, há uma ampla discussão sobre os critérios de diagnóstico para essa desordem. Além do cortisol basal, algumas publicações analisaram o papel de outros testes, tais como o teste de estímulo com ACTH (cortrosina), com doses baixas (1 mg) ou altas (250 mg), cortisol livre, cortisol salivar, teste da metirapona e outros. O objetivo desta revisão foi resumir os resultados dos artigos mais importantes que buscaram definir os critérios de diagnóstico para a CIRCI. Também sugerimos uma abordagem para o diagnóstico da CIRCI e deixamos claro que a decisão sobre a terapia com esteroides em pacientes em choque séptico é uma questão separada da IAR.

Combined 17α-hydroxylase/17,20-lyase deficiency due to p.R96W mutation in the CYP17 gene in a Brazilian patient / Deficiência combinada de 17α-hidroxilase/17,20 liase devido à mutação p.R96W no gene CYP17 em um paciente brasileiro

Congenital adrenal hyperplasia (CAH) resulting from 17α-hydroxylase/17,20-lyase deficiency is a rare autosomal recessive disease and the second most common form of CAH in Brazil. We describe the case of a Brazilian patient with CYP17 deficiency (17α-hydroxylase/17,20-lyase deficiency) caused by a homozygous p.R96W mutation on exon 1 of the CYP17 gene, an unusual genotype in Brazilian patients with this form of CAH. The patient, raised as a normal female, sought medical care for lack of pubertal signs and primary amenorrhea at the age of 16 years. At evaluation, the presence of a 46,XY karyotype, hypertension and hypokalemia were observed. We emphasize the recognition of CYP17 deficiency in the differential diagnosis of cases of hypergonadotrophic hypogonadism and hypertension in young patients who need specific treatment for both situations.

A hiperplasia adrenal congênita (HAC), em razão da deficiência de 17α-hidroxilase/17,20-liase, é uma doença autossômica recessiva rara e a segunda causa mais comum de HAC no Brasil. Descrevemos o caso de um paciente brasileiro portador da deficiência 17α-hidroxilase/17,20- liase (CYP17) em homozigose para a mutação p.R96W no éxon 1 do gene da CYP17A1, uma mutação incomum entre os casos brasileiros descritos com essa forma de HAC. Esse paciente, criado como um indivíduo normal do sexo feminino, procurou atendimento por ausência de sinais puberais e amenorreia primária aos 16 anos de idade. Durante a avaliação, constataram-se um cariótipo 46,XY e a presença de hipertensão e hipocalemia. Enfatizamos o reconhecimento da deficiência da CYP17 dentre os possíveis diagnósticos em um paciente jovem com hipogonadismo hipergonadotrófico e hipertensão, os quais necessitam de tratamento particularizado para ambas as situações.