Adrenal insufficiency and pregnancy

INTRODUCTION: Adrenal insufficiency is a disorder characterized by the failure of adrenocortical function because of distorted function of hypothalamic-pituitary- adrenal (HPA) axis. Pregnancy is a state of a physiological glucocorticoid excess as the HPA axis is functioning at a higher level. PURPOSE OF REVIEW: The aim of the present review was to shed light on current evidence of adrenal insufficiency management during pregnancy, along with maternal and neonatal outcomes. RECENT FINDINGS: A recent multicenter study under the auspices of the European Network for the Study of Adrenal Tumours (ENSAT) presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone (or mineralocorticoids when needed according to the level of disorder) replacement treatment, increased rates of caesarean section, preterm delivery and adrenal crises along with peripartum and postpartum complications but no maternal or neonatal fatality. These data were in agreement with those obtained from previously published studies. CONCLUSION: The limited published evidence is in line with the present guidelines as real-life data did not document any increased fatality among pregnant women or newborns. Prospective data with prolonged follow-up are needed to shed more light on appropriate dose adjustments to avoid the risks of under-replacement or over-replacement of glucocorticoid and/or mineralocorticoid drugs and their sequelae. SUMMARY: A recent multicenter study by ENSAT presented real-life data of pregnant women with adrenal insufficiency documenting an increased use of hydrocortisone as replacement treatment during pregnancy, along with an increased rate of caesarean section and preterm delivery, adrenal crises, peripartum and postpartum complications but no maternal or neonatal fatality. These data are in agreement with those of a previously published study and also confirm the statements made by the recent guidelines. Prospective data are needed aiming to develop precise therapeutic protocols during each trimester of pregnancy according to the different causes of adrenal insufficiency. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved

Ectopic ACTH syndrome

Ectopic adrenocorticotropin secretion (EAS) accounts for 10-15% of cases of Cushing's syndrome and comprises a spectrum of tumours from undetectable isolated lesions to widespread metastatic and aggressive malignancies. EAS is often associated with severe hypercortisolaemia causing hypokalaemia, diabetes, generalized infections, hypertension and psychotic reactions. Surgical resection of the primary lesion, achievable with a curative intent in about 40% of patients with EAS, is associated with complete remission in up to 80% of such cases. It is therefore mandatory to localize the source of ectopic ACTH hypersecretion in order to stage the disease and adopt optimal treatment modalities. Modern cross-sectional imaging techniques can identify the majority of the ACTH secreting lesions, either initially or at follow-up reassessment. However, in approximately 10-20% of patients with EAS, the source of ACTH hypersecretion remains occult in spite of extensive investigation and prolonged follow-up. In such cases, control of the hypercortisolemia can be achieved with long-term adrenolytic medication. When conditions require a prompt and definitive resolution of the hypercortisolaemia (i.e. as in pregnancy), bilateral adrenalectomy remains an alternative option. This review focuses on the clinical features, diagnostic pitfalls, management and long-term follow-up of the EAS based on the extensive experience of major referral centres. Copyright © 2006 S. Karger AG

The diagnosis and management of parasellar tumours of the pituitary

The sellar and parasellar region is an anatomically complex area where a number of neoplastic, inflammatory, infectious, developmental and vascular diseases can develop. Although most sellar lesions are due to pituitary adenomas, a number of other pathologies involving the parasellar region can present in a similar manner. The diagnosis of such lesions involves a multidisciplinary approach, and detailed endocrinological, ophthalmological, neuroimaging, neurological and finally histological studies are required. Correct diagnosis prior to any intervention is essential as the treatment of choice will be different for each disorder, particularly in the case of primary malignant parasellar tumours. The complexity of structures that define the parasellar region can produce a variety of neoplastic processes, the malignant potential of which relies on histological grading. In the majority of parasellar tumours, a multimodal therapeutic approach is frequently necessary including surgery, radiotherapy, primary or adjuvant medical treatment and replacement of apparent endocrine deficits. Disease-specific medical therapies are mandatory in order to prevent recurrence or further tumour growth. This is particularly important as neoplastic lesions of the parasellar region tend to recur after prolonged follow-up, even when optimally treated. Apart from the type of treatment, identification of clinical and radiological features that could predict patients with different prognosis seems necessary in order to identify high-risk patients. Due to their rarity, central registration of parasellar tumours is required in order to be able to provide evidence-based diagnostic and mainly therapeutic approaches. © 2008 Society for Endocrinology

Treatment of advanced neuroendocrine tumours with radiolabelled somatostatin analogues

Neuroendocrine tumours (NETs) constitute a heterogeneous group of tumours that frequently express cell membrane-specific peptide receptors, such as somatostatin receptors (SSTRs), and of which gastroenteropancreatic (GEP), carcinoid and pancreatic islet cell tumours exhibit the highest expression of SSTRs. Radiolabelled receptor-binding somatostatin analogues (octreotide and lanreotide) act as vehicles to guide radioactivity to tissues expressing SSTRs, and can thus be used for their diagnosis and treatment. After the localization of NETs bearing SSTRs with 111In-octreotide (OctreoScan), a number of radioisotopes with different physical properties have been used for their treatment. The administration of high doses of the Auger electron and γ-emitter 111In-diethylenetriaminepenta-acetic acid (DTPA) 0,octreotide in patients with metastatic tumours has been associated with considerable symptomatic improvement but relatively few and short-lived objective tumour responses. The use of another radiolabelled somatostatin analogue coupled with 90Y, a pure β-emitter, 90Y-1,4,7,10-tetraazacyclododecane-N,N′N″N‴- tetraacetic acid (DOTA)0,Tyr3,octreotide ( 90Y-DOTATOC, OctreoTher), was associated with 10-30% objective tumour response rates, and appears to be particularly effective in larger tumours. 111In- and 90Y-DOTA-lanreotide has also been used for the treatment of NETs although its therapeutic efficacy is probably inferior to that of octreotide-based radiopharmaceuticals. More recently, treatment with 177Lu-DOTA0,Tyr3octreotate ( 177Lu-DOTATATE), which has a higher affinity for the SSTR subtype 2, resulted in approximately 30% complete or partial tumour responses; this radiopharmaceutical is particularly effective in smaller tumours. Furthermore, treatment using both 90Y-DOTATOC and 177Lu-DOTA 0,Tyr3octreotate seems promising, as the combination of these radiopharmaceuticals could be effective in tumours bearing both small and large lesions. Tumour regression is positively correlated with a high level of uptake on 111In-octreotide scintigraphy, limited tumour mass and good performance status. In general, better responses have been obtained in GEP tumours than other NETs. The side effects of this form of therapy are relatively few and mild, particularly when kidney-protective agents are used. Treatment with radiolabelled somatostatin analogues presents a promising tool for the management of patients with inoperable or disseminated NETs, and particularly GEP tumours. © 2005 Society for Endocrinology Printed in Great Britain

The Medical Therapy of Craniopharyngiomas: The Way Ahead

Craniopharyngiomas, which are categorized as adamantinomatous (ACPs) or papillary (PCPs), have traditionally been treated with surgery and/or radiotherapy, although when the tumors progress or recur, therapeutic possibilities are very limited. Following recent advances in their molecular pathogenesis, new medical therapeutic options have emerged. Evidence Acquisition: The search strategy that we selected to identify the appropriate evidence involved the following medical subject headings (MeSH) terms: ("Craniopharyngioma" [MeSH] AND "Craniopharyngioma/drug therapy" [MeSH]) NOT ("review" [Publication Type] OR "review literature as topic" [MeSH Terms] OR "review" [All Fields]) AND ("2009/05/01" [PDat]: "2019/04/28" [PDat]). Evidence Synthesis: Mutations of β-catenin causing Wnt activation with alterations of the MEK/ERK pathway are encountered in the great majority of patients with ACPs; specific alterations also stratify patients to a more aggressive behavior. In most PCPs there is primary activation of the Ras/Raf/MEK/ERK pathway secondary to BRAF-V600E mutations. BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCPs producing clinically useful and, in some cases, sustained responses. In contrast to PCPs, drugs targeting β-catenin and its downstream MAPK pathway in ACPs have so far only been used in in vitro studies, but there appear to be promising new targets clinically. Conclusions: The identification of specific genetic alterations in patients with craniopharyngiomas has expanded the therapeutic options, providing evidence for a customized approach using newer molecular agents. More studies including a larger number of carefully selected patients are required to evaluate the response to currently available and evolving agents alone and in combination. Copyright © 2019 Endocrine Society

Nonneuroendocrine Neoplasms of the Pituitary Region

Context Although most sellar lesions are related to pituitary adenomas, the region gives rise to a variety of neoplasms that can be associated with substantial morbidity and/or mortality. Design Information from reviews and guidelines of relevant societies dealing with such neoplasms, as well as articles that have provided new developments that made important contributions to their pathogenesis and treatment up to 2018, were obtained: public indexes such as PubMed/MEDLINE were used with the relevant search items. Results Sellar neoplasms have a worse outcome than pituitary adenomas that is related not only to their natural history but also to side effects of therapies and evolving endocrine and/or hypothalamic deficiencies. Recent imaging advances have established the radiological fingerprint of some of these neoplasms, and several chromosomal aberrations have also been identified. Although established approaches along with new surgical and radiotherapeutic approaches remain the main treatment modalities, recent evidence has provided insight into their molecular pathogenesis involving, other than chemotherapy, treatments with targeted agents as in gliomas and craniopharyngiomas bearing BRAF mutations. Development of predictive markers of recurrences may also identify high-risk patients, including proliferative markers and expression of the progesterone receptor in meningiomas, and lead to less aggressive surgery. Owing to the rarity and complexity of these neoplasms, patients should be managed in dedicated centers. Conclusions The diagnosis and management of sellar neoplasms necessitate a multidisciplinary approach. Following evolving recent advances in their diagnosis and therapy, such a multidisciplinary approach needs to be extended to establish evidence-based diagnostic and management plans. © 2019 Endocrine Society

Expression of connective tissue growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their clinico-pathological significance

Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; n=58) and midgut NETs (n=38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1 cmbut only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage. © 2011 Society for Endocrinology

Advances and Current Concepts in the Medical Management of Gastroenteropancreatic Neuroendocrine Neoplasms

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous group of tumors presenting as localised or metastatic disease and in a subset with distinct clinical syndromes. Treatment is aimed at controlling the functional syndrome, eradicating the tumor, and/or preventing further tumor growth. Surgery is the treatment of choice in removing the primary tumor and/or reducing tumor burden but cannot be applied to all patients. Somatostatin analogs (SS-analogs) obtain control of functional syndromes in the majority of GEP-neuroendocrine tumors (NETs); phase III trials have shown that SS-analogs can be used as first-line antiproliferative treatment in patients with slow-growing GEP-NETs. The role of the recently approved serotonin inhibitor, telotristat ethyl, and gastrin receptor antagonist, netazepide, is evolving. Streptozotocin-based chemotherapy has been used for inoperable or progressing pancreatic NENs but the orally administered combination of capecitabine/temozolomide is becoming more popular due to its better tolerability and potential effect in other GEP-NENs. Phase III trials have shown efficacy of molecular targeted therapies in GEP-NETs and of radionuclide treatment in patients with midgut carcinoid tumors expressing somatostatin receptors. Most patients will develop disease progression necessitating further therapeutic options. A combination of currently available treatments along with the molecular signature of each tumor will guide future treatment. © 2017 Krystallenia I. Alexandraki et al

Clinical review: Diagnosis and management of pituitary carcinomas

Pituitary carcinomas are rare, making up some 0.2% of all pituitary tumors, but represent a particular challenge to clinical practice. The diagnosis of a pituitary carcinoma requires evidence of metasta tic disease, either outside the central nervous system (CNS) or as separate noncontiguous foci within the CNS. They may present as typical pituitary adenomas, which reveal their malignant character only as time progresses, or as peculiarly aggressive tumors ab initio. Recent changes in histopathological classification have clarified many of the features of such tumors, including immunohistochemical staining for Ki-67 and p53, but to date none has been found to be pathognomonic. The majority of carcinomas are secretory, usually arising from corticotroph tumors or prolactinomas, but all histological types and secretory patterns are represented. Treatment is by surgery, transsphenoidal wherever possible, and conventional and stereotactic radiotherapy, but ultimately, a plethora of therapies may be required, including various attempts at medical therapy. Chemotherapy in some instances probably prolongs survival, but, in general, their progress from the diagnosis of carcinomatous changes is progressive and inexorable. However, we do not believe there will be any real prospect of long-term survival until the development and use of therapies targeted at specific molecular abnormalities. Copyright © 2005 by The Endocrine Society