How to manage intolerance to dopamine agonist in patients with prolactinoma.

PURPOSE: Dopamine agonists (DA) are the gold-standard for prolactinoma and hyperprolactinemia treatment. Intolerance to DA leading to drug drop out occurs in 3 to 12% of cases. We provide here a review of published data about DA intolerance and present a case report concerning the use of intravaginal cabergoline. METHODS: We review the literature on the definition, the pathogenesis, frequency and management of DA intolerance. In addition, the review provides strategies to enhance tolerability and avoid precocious clinical treatment withdrawal. RESULTS: Cabergoline is often cited as the most tolerable DA and its side effects tend to ameliorate within days to weeks. Restarting the same drug at a lower dose or switching to another DA can be used in cases of intolerance. The vaginal route can be tried specifically if there are gastrointestinal side effects in the oral administration. Symptomatic treatment could be attempted, although mainly based on a strategy used in other diseases. CONCLUSIONS: Due to limited data, no guidelines have been developed for the management of intolerance in DA treatment. The most frequent management is to perform transsphenoidal surgery. Nevertheless, this manuscript provides data derived from published literature and expert opinion, suggesting new approaches to this clinical issue.

High accuracy of bilateral and simultaneous petrosal sinus sampling with desmopressin for the differential diagnosis of pediatric ACTH-dependent Cushing's syndrome.

PURPOSE: To analyze the bilateral and simultaneous petrosal sinus sampling (BIPSS) in a subgroup of children and adolescents with ACTH-dependent Cushing's syndrome (ADCS) METHODS: Retrospective study in a tertiary reference center. From 1993 and 2017, 19 children and adolescents (PED) were submitted to the BIPSS, median age of 14 years (range 9-19 years), 53% were males, 18 had Cushing's disease (CD) and one had ectopic ACTH syndrome (EAS). All procedures were performed with 10 µg of intravenous desmopressin. RESULTS: The catheter positioning was successful in all cases. The central ACTH gradient was met in 17/19 cases. At baseline, central gradient occurred in 16/19 (84%) with gradient values of 7.2 ± 6.0. After stimulation, there was an increase in the center-periphery gradient values (33.6 ± 44.3). In one case, central gradient was defined only after stimulation. Two cases presented without a central gradient; one case of CD with a false-negative and one EAS case. Lateralization occurred in all cases with a central gradient. Confirmation of the tumor location presumed by the procedure with the surgical description occurred in 60% of the cases. The BIPSS in this PED subgroup of ADCS presented a sensitivity of 94.4% and specificity of 100%. There were no complications of the procedure. CONCLUSION: In a series of children and adolescents with ADCS, BIPSS was safe and highly accurate in defining the central to peripheral ACTH gradient using desmopressin as secretagogue. Nevertheless, there was a limited value of the ACTH-gradient between the petrosal sinuses for the tumor location.

Pregnancy after pituitary surgery does not influence the recurrence of Cushing's disease.

PURPOSE: Pregnancy is associated with the activation of the hypothalamus-pituitary-adrenal axis, which can cause a misdiagnosis of Cushing's syndrome. The aim of this study is to evaluate the impact of pregnancy after pituitary surgery on the recurrence rate in Cushing's disease (CD) patients. METHODS: This was a retrospective study in a tertiary center. Between 1990 and 2020, 355 CD patients underwent pituitary surgery. Of those, we included 113 female patients who were ≤ 45 years old (median age of 32 years, 14-45), PS remission, a follow-up of ≥6 months (median of 122 months, 6-402) and an available obstetric history. Recurrence was defined as the diagnosis of Cushing's syndrome via at least two altered first-line methods. The patients were divided into two subgroups according to pregnancy: no pregnancy or pregnancy prior to CD diagnosis (NP/PP) and pregnancy after CD pituitary surgery (PA). RESULTS: Overall, recurrence occurred in 43 out of 113 patients (38%). A higher recurrence rate was seen in the PA subgroup (11/22, 50%), but there was no significant difference between the NP/PP subgroup (32/91, 35%). No difference in survival-free recurrence (SFR) was found between NP/PP and PA subgroups. The lower SFR was related to a higher PS plasma ACTH and normal pituitary at pathological analyses. CONCLUSIONS: There was no difference in the recurrence rate in patients according to pregnancy history. Other studies with higher numbers of patients are needed to confirm these data.

Role for postoperative cortisol response to desmopressin in predicting the risk for recurrent Cushing's disease.

UNLABELLED: In the early postoperative period of Cushing's disease patients, desmopressin may stimulate ACTH secretion in the remnant corticotrophic tumour, but not in nontumour suppressed cells. OBJECTIVE: The aim of this study is to evaluate the serum cortisol responses to desmopressin after pituitary surgery, establishing an optimal cut-off for absolute increment (Delta) of serum cortisol (F) suitable to predict recurrence risk. DESIGN: Retrospective case record study. PATIENTS: Fifty-seven Cushing's disease patients submitted to pituitary surgery and desmopressin stimulation in the early postoperative with a long-term follow-up (20-161 months) were studied. METHODS AND MEASUREMENTS: Serum cortisol levels after desmopressin test (10 microg i.v.) 15-30 days after adenomectomy were used to determine DeltaF (absolute increment of F: F peak - F baseline). Sensitivity and specificity of DeltaF were calculated and a ROC curve was performed to establish an optimal cut-off for DeltaF to predict recurrence risk. RESULTS: Fifteen patients had immediate postoperative failure (basal F > 165 nmol/l; 6 microg/dl) and one patient was lost during the follow-up. Forty-one patients achieved initial remission and were followed-up. Five of 11 patients who recurred had DeltaF > 193 nmol/l (7 microg/dl), but none of 30 patients who remained in prolonged remission showed DeltaF > 193 nmol/l after postoperative desmopressin stimulation. CONCLUSIONS: Persistence of cortisol response (DeltaF > 193 nmol/l) to desmopressin in the early postoperative period can help to identify Cushing's disease patients with initial remission who present risk for later recurrence.

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.

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.

Thickened Pituitary Stalk Associated with a Mass in the Sphenoidal Sinus: An Alarm to Suspect Hypophysitis by Immunoglobulin G4?

Introduction Hypophysitis is a chronic inflammation of the pituitary gland of complex and still incompletely defined pathogenesis. It belongs to the group of non-hormone-secreting sellar masses, sharing with them comparable clinical presentation and radiographic appearance. Objectives Describe the case of immunoglobulin G4 (IgG4)-related hypophysitis presenting as a mass in the sphenoid sinus. Resumed Report A 40-year-old Brazilian man had a diagnosis of central diabetes insipidus since 2001 associated with pituitary insufficiency. Pituitary magnetic resonance imaging revealed a centered pituitary stalk with focal nodular thickening and the presence of heterogeneous materials inside the sphenoid sinus. The patient was treated with testosterone replacement therapy. Laboratory results revealed increased IgG4 serum. Conclusion IgG4-related hypophysitis should be considered in patients with pituitary insufficiency associated with sellar mass and/or thickened pituitary stalk. IgG4 serum measurement for early diagnosis of IgG4-related hypophysitis should be performed.

Persistence of intrasellar trigeminal artery and simultaneous pituitary adenoma: description of two cases and their importance for the differential diagnosis of sellar lesions.

Persistent trigeminal artery (PTA) is the most frequent embryonic communication between the carotid and vertebrobasilar systems. However, hormonal changes or the association of PTA with other sellar lesions, such as pituitary adenomas, are extremely rare. The aim of the present study was to report two patients with intrasellar PTA and simultaneous pituitary adenoma in order to emphasize the importance of differential diagnoses for sellar lesions. Case 1. A female patient, 41 years old, was admitted with a history of chronic headache (> 20 years). Pituitary magnetic resonance imaging (MRI) showed a rounded lesion in the left portion of the pituitary gland suggestive of adenoma (most likely clinically non-functioning adenoma). In addition to this lesion, the MRI demonstrated ecstasy of the right internal carotid artery and imaging suggestive of an intrasellar artery that was subsequently confirmed by an angio-MRI of the cerebral vessels as PTA. Case 2. A female patient, 42 years old, was admitted with a history of amenorrhea and galactorrhea in 1994. Laboratorial investigation revealed hyperprolactinemia. Pituitary MRI showed a small hyposignal area in the anterior portion of pituitary gland suggestive of a microadenoma initiated by a dopaminergic agonist. Upon follow-up, aside from the first lesion, the MRI showed a well delineated rounded lesion inside the pituitary gland, similar to a vessel. Angio-MRI confirmed a left primitive PTA. Failure to recognize these anomalous vessels within the sella might lead to serious complications during transsphenoidal surgery. Therefore, although their occurrence is uncommon, a working knowledge of vascular lesions in the sella turcica or pituitary gland is important for the differential diagnosis of pituitary lesions, especially pituitary adenomas.

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.

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.

Thickened pituitary stalk associated with a mass in the sphenoidal sinus: an alarm to suspect hypophysitis by immunoglobulin g4?

Introduction Hypophysitis is a chronic inflammation of the pituitary gland of complex and still incompletely defined pathogenesis. It belongs to the group of non-hormonesecreting sellar masses, sharing with them comparable clinical presentation and radiographic appearance. Objectives Describe the case of immunoglobulin G4 (IgG4)-related hypophysitis presenting as a mass in the sphenoid sinus. Resumed Report A 40-year-old Brazilian man had a diagnosis of central diabetes insipidus since 2001 associated with pituitary insufficiency. Pituitary magnetic resonance imaging revealed a centered pituitary stalk with focal nodular thickening and the presence of heterogeneous materials inside the sphenoid sinus. The patient was treated with testosterone replacement therapy. Laboratory results revealed increased IgG4 serum. Conclusion IgG4-related hypophysitis should be considered in patients with pituitary insufficiency associated with sellar mass and/or thickened pituitary stalk. IgG4 serum measurement for early diagnosis of IgG4-related hypophysitis should be performed.

Persistence of intrasellar trigeminal artery and simultaneous pituitary adenoma: description of two cases and their importance for the differential diagnosis of sellar lesions / Persistência da artéria trigeminal intrasselar e simultâneo adenoma de hipófise: descrição de dois casos e importância para o diagnóstico diferencial das lesões selares

Persistent trigeminal artery (PTA) is the most frequent embryonic communication between the carotid and vertebrobasilar systems. However, hormonal changes or the association of PTA with other sellar lesions, such as pituitary adenomas, are extremely rare. The aim of the present study was to report two patients with intrasellar PTA and simultaneous pituitary adenoma in order to emphasize the importance of differential diagnoses for sellar lesions. Case 1. A female patient, 41 years old, was admitted with a history of chronic headache (> 20 years). Pituitary magnetic resonance imaging (MRI) showed a rounded lesion in the left portion of the pituitary gland suggestive of adenoma (most likely clinically non-functioning adenoma). In addition to this lesion, the MRI demonstrated ecstasy of the right internal carotid artery and imaging suggestive of an intrasellar artery that was subsequently confirmed by an angio-MRI of the cerebral vessels as PTA. Case 2. A female patient, 42 years old, was admitted with a history of amenorrhea and galactorrhea in 1994. Laboratorial investigation revealed hyperprolactinemia. Pituitary MRI showed a small hyposignal area in the anterior portion of pituitary gland suggestive of a microadenoma initiated by a dopaminergic agonist. Upon follow-up, aside from the first lesion, the MRI showed a well delineated rounded lesion inside the pituitary gland, similar to a vessel. Angio-MRI confirmed a left primitive PTA. Failure to recognize these anomalous vessels within the sella might lead to serious complications during transsphenoidal surgery. Therefore, although their occurrence is uncommon, a working knowledge of vascular lesions in the sella turcica or pituitary gland is important for the differential diagnosis of pituitary lesions, especially pituitary adenomas.

Persistência da artéria trigeminal (PAT) é a comunicação embrionária mais frequente entre os sistemas carotídeo e vertebrobasilar. No entanto, alterações hormonais ou associação de PAT com outras lesões selares, como adenomas hipofisários, são extremamente raros. O objetivo do presente estudo foi relatar dois pacientes com PAT intrasselar e concomitante adenoma hipofisário e enfatizar a importância para o diagnóstico diferencial de lesões selares. Caso 1. Paciente do sexo feminino, 41 anos, admitida com história de cefaleia crônica (> 20 anos). Ressonância magnética (RM) de hipófise mostrou imagem arredondada na porção esquerda da glândula sugestiva de adenoma (provavelmente adenoma clinicamente não funcionante). Adicionalmente, a RM demonstrou ectasia da artéria carótida interna direita e imagem sugestiva de artéria intrasselar, posteriormente confirmada por angio-RM dos vasos cerebrais como PAT. Caso 2. Paciente do sexo feminino, 42 anos, admitida com história de amenorreia e galactorreia em 1994. A investigação laboratorial revelou hiperprolactinemia. RM de hipófise mostrou pequena área de hipossinal na porção anterior da glândula sugestiva de microadenoma, sendo iniciado agonista dopaminérgico. Na evolução, além da primeira lesão, a RM mostrou uma imagem arredondada bem delimitada dentro da glândula pituitária semelhante a vaso sanguíneo. Angio-RM confirmou PAT primitiva esquerda. A falta de reconhecimento de tais vasos anômalos dentro da sela túrcica pode levar a sérias complicações durante a cirurgia transesfenoidal. Portanto, apesar de sua ocorrência não ser comum, o conhecimento de lesões vasculares dentro da sela túrcica ou glândula hipofisária é importante para o diagnóstico diferencial de lesões da hipófise, especialmente com adenomas hipofisários.