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.

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.

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 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.

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.

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.

[Growth hormone (GH) and IGF-I assays: methodological aspects and its implications in acromegaly diagnosis and follow-up]. / Ensaios para a medida de hormônio do crescimento (GH) e IGF-I: aspectos metodológicos e suas implicações no diagnóstico e seguimento da acromegalia.

Growth hormone quantification in serum is essential for confirming or ruling out its excess. The absence of clinical criteria sufficiently sensitive to evaluate the treatment success enables GH as the key diagnostic procedure and for that, its measurements must be done in a reliable way and must allow uniform interpretation. Several different biochemical criteria for remission have been suggested in the past, including a random GH measurement less than 2.5 microg/l, mean GH value from a day curve less than 2.5 microg/l, nadir GH value after an oral glucose tolerance test (OGGT) less than 1.0 microg/l and a normal age-related IGF-I level. The importance of adequate treatment is highlighted by data indicating that lowering GH levels to less than 2.5 microg/l reverses the premature mortality of acromegaly. With the advances of ultrasensitive assays for GH measurement, strictest remission criteria to determine remission or cure were necessary. In this review, we describe the changes of assay methodology and its consequences in serum GH results and cut off point values to define activity and remission of acromegaly.

Prospective evaluation of transsphenoidal pituitary surgery in 108 patients with Cushing's disease.

Transsphenoidal pituitary surgery (TSS) remains the treatment of choice for Cushing's disease (CD). Despite the widespread acceptance of this procedure as the first line treatment in CD, the indication of a second TSS in not cured or relapsed DC patients is not consensus. We report the results of TSS in 108 patients with CD (a total of 117 surgeries). The mean postoperative follow-up period was 6 years. Remission was defined as clinical and laboratorial signs of adrenal insufficiency, period of glucocorticoid dependence, serum cortisol suppression on oral 1-mg dexamethasone overnight suppression test and clinical remission of hypercortisolism. We evaluated 103 patients with CD by the time of the first TSS. Fourteen patients underwent second TSS (5 had already been operated in others centers; in 5 patients the first surgery was not curative; in 4 patients CD relapsed). Remission rates were 85.4% and 28.6% (p < 0.001) after first and second TSS, respectively. In microadenomas, remission rates were higher than macroadenomas (94.9% vs. 73.9%; p = 0.006). In patients with negative pituitary imaging remission rates were 71.4% (p = 0.003; vs. microadenomas). Postoperative complications were: transient diabetes insipidus, definitive diabetes insipidus, hypopituitarism, stroke and one death. Only hypopituitarism was more frequent after second TSS (p = 0.015). In conclusion, TSS for CD is an effective and safe treatment. The best remission rates were observed at the first surgery and in microadenomas. The low remission rates after a second TSS suggest that this approach could not be a good therapeutic choice when the first one was not curative.

[Childhood hypoglycemia: results of prospective evaluation protocols in children with up to 1 year of age]. / Hipoglicemia na infância: resultados de um protocolo de avaliação prospectiva em crianças com até 1 ano de idade.

The aim of this study is to present the experience of applying hypoglycemia evaluation protocol. We performed a prospective study with 13 children with hypoglycemia symptoms at the Hospital of Clinicas of Porto Alegre, with range age 5.3+/-4.5 months and eight patients are female. The patients had been submitted to glucagon fasting test and blood glucose, lactate, pH, C peptide, insulin, fatty acids, TSH, GH, cortisol, and urine ketones were measured. Eight patients presented persistent hypoglycemia and five presented transitory hypoglycemia. The most frequent diagnosis was persistent hyperinsulinism. We suggest the use of a simple protocol for the evaluation of hypoglycemia, which contemplates the identifications of the main etiologies in children and facilitates the handling of these patients.

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.

[Prevalence of the use of anabolic agents among strength training apprentices in Porto Alegre, RS]. / Prevalência do uso de agentes anabólicos em praticantes de musculação de Porto Alegre.

This study aimed to determine through a questionnaire applied to interviewers, the current or past use of anabolic androgenic steroids (AAS), as well as other hormones (OH), and other medicines (OM), food supplement and illicit drugs among strength training apprentices in the city of Porto Alegre, RS. We interviewed 288 subjects draw from a sample of 13 gyms. The prevalence of current and past use of AAS was about 11.1% (32/288), OH 5.2% (16/288) and OM 4.2% (12/288). The most used AAS were nandrolone and stanozolol; the OH were gonadotropin, triiodothyronine (T3) and OM, like lipostabil, diuretics and veterinary medicines (Monovin E). The most frequent side-effects were behavioral such as humor oscillation, irritability and hostility, and endocrine disturbances such as acne and increased or decreased libido. When analyzed together with other hormones in a variable named "hormonal agents" (AH), AAS presented a statistical difference (p< 0.05) among genders considering that the most frequent use of AH occurred among men and those who consume food supplements. The comparison of these findings to other national and international results is difficult due to the epidemiological design. Even if it is considered, the observed prevalence suggests that preventive attitudes as well as special care in the orientation and education of this population must be taken.

[Pituitary abscess simulating apoplexy]. / Abscesso hipofisário simulando apoplexia.

A pituitary abscess is a rare pathology, but it must be considered when evaluating sellar masses, since its prognosis depends on surgical drainage and on the use of specific antibiotics. The main clinical manifestation is chronic headache, and it is not always associated with the identification of a site of infection, which diminishes the probability of including it in diagnostic hypotheses. The case is presented of a patient with a pituitary abscess and a previous history of adenoma that had been operated on, recent onset headache and acquired hypopituitarism whose initial diagnosis was pituitary apoplexy.

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.

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.

[Granulosa-stromal tumor of the ovary: a case of mixed germ cell-cord stromal tumor of the ovary with endocrinological considerations]. / Puberdade precoce associada a tumor misto ovariano (células germinativas- estroma-cordão sexual): aspectos clínicos, diagnósticos e manejo de um caso.

Granulosa-stromal tumors comprise 5 to 8% of all primary ovarian neoplasms. The first clinical manifestation is precocious puberty in most prepuberal patients. We report a case of mixed germ cell-cord stromal tumor of ovary in a 7.2 years old girl, who presented with isosexual pseudo-precocious puberty of progressive outcome. Serum testosterone, estradiol and 17alphaOH-progesterone levels were increased. Abdominal-pelvic ultrasound revealed a right ovarian mass. Unilateral salpingo-oophorectomy was performed with complete resection of the tumor. The patient is well 7 years after surgery with normal pubertal and growth development and no signs of tumor relapse. We review the clinical manifestations of ovarian tumors, classification and staging of sex cord-stromal tumors, follow-up, tumor markers, treatment and prognosis.

[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.

[Prevalence of adrenal incidentaloma at computed tomography (chest and abdominal) in a general hospital in Brazil]. / Prevalência de lesão adrenal incidental em pacientes submetidos a tomografia computadorizada de tórax e abdome em um hospital geral brasileiro.

OBJECTIVE: To prospectively determine the prevalence of incidental adrenal lesions at computed tomography (CT) at an University Hospital in Brazil. PATIENTS AND METHOD: A cross-sectional prospective study was performed to evaluate 3,382 consecutive patients with no known adrenal disease or malignancies who underwent chest and abdominal CT scans over a ten-month period. The cases of adrenal incidentaloma were defined by the presence of any change in gland contour, size or density. Kappa values were calculated, evaluating the intra and inter-observer agreement. RESULTS: One hundred and one incidental adrenal masses were identified, corresponding to 83 cases and a prevalence of 2.5% (CI 95%: 1.0%-3.2%). Male patients presented a higher prevalence of incidentaloma than female (3.3% vs. 1.5%; p= 0.01). There was a significant association between older age and higher frequency of incidentaloma. Kappa of 0.76 and 0.83 (good and excellent agreement, respectively), were obtained in evaluating the intra and inter-observer agreements. CONCLUSIONS: The prevalence of adrenal incidentaloma detected by CT was similar to that of various published retrospective clinical series. The two factors that independently influenced the distribution of incidentalomas were older age and being male.

[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.

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.