Secondary diabetes mellitus in pheochromocytomas and paragangliomas.

Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.

Recent advances in understanding and managing pituitary adenomas.

Pituitary adenomas (PAs) are common intracranial tumors. Despite their benign nature, PAs may cause a significant burden of disease, leading to either hormonal disturbances or local compression. A subset of PAs presents an aggressive behavior that remains difficult to predict, and in rare cases they metastasize. Therefore, early diagnosis and treatment are important. Advances in molecular pathology have improved the understanding of their pathogenesis and offer opportunities to identify and target novel pathways. Improved imaging and functional molecular techniques precisely detect even very small tumors and guide targeted treatment. Transsphenoidal surgery is the first-line treatment for the majority of PAs, and advances in the field of endoscopic neurosurgery offer excellent outcomes. Dopamine agonists (DAs) are traditionally the first-line treatment for prolactinomas. For patients with acromegaly, first- and second-generation somatostatin analogues (SSAs) are applied when surgery is not successful or not indicated. For Cushing's disease (CD), drugs targeting adrenal steroidogenesis, somatostatin receptors in the pituitary, and glucocorticoid receptors are used to treat hypercortisolism in patients with persistent or recurrent CD, for those who are not good surgical candidates, and as a bridge treatment for those who have undergone radiation treatment until cortisol levels are controlled. Temozolomide (TMZ) is the first-line chemotherapy for aggressive PAs, but new experimental therapies, like the anti-vascular endothelial growth factor (anti-VEGF) therapy, mechanistic target of rapamycin (mTOR) inhibitors, tyrosine kinase inhibitors, and cell cycle and checkpoint inhibitors, are now available. Radiotherapy is offered to patients with residual, recurrent, or progressive tumors. Modern techniques in radiotherapy planning and delivery are able to deliver high doses to the target tissue while sparing vital structures. As we familiarize ourselves with the biological behavior of PAs and our therapeutic armamentarium expands, the next goal is to tailor and personalize treatment to each individual patient so as to achieve the best outcome.

Pre- and peri-operative characteristics, complications and outcomes of patients with biochemically silent pheochromocytomas; a case series.

PURPOSE: Pheochromocytomas are rare tumors and biochemically silent ones with normal catecholamine levels are even rarer. Up to date, biochemically inactive pheochromocytomas are poorly investigated. We aimed to systematically assess the pre- and peri-operative characteristics and the outcomes of patients with these tumors who had been treated and followed-up in 2 tertiary centers. METHODS: Clinical, laboratory and imaging data, treatment outcomes and follow-up of biochemically silent pheochromocytoma patients were recorded. RESULTS: Ten patients (5 men) [median age at diagnosis 52.5 years (24-72)] were included. Adrenal masses were incidentally discovered in all patients except from one who presented with pheochromocytoma-related manifestations. Twenty-four-hour urine metanephrine and normetanephrine levels were in the low-normal, normal and high-normal range in 4, 4 and 2 patients and in 1, 6 and 3 patients, respectively. Tumors were unilateral [median size 46 mm (17-125)] and high density on pre-contrast CT imaging or high signal intensity on T2-weighted MRI scans were found in all cases. Pre-operatively, 5 patients were treated with phenoxybenzamine [median total daily dose 70 mg (20-100)]. Intra-operatively, 4 patients developed hypertension requiring vasodilator administration and 8 developed hypotension; vasoconstrictors were required in 5 cases. One patient, not pre-operatively treated with phenoxybenzamine, developed Takotsubo cardiomyopathy. During a median 24-month (12-88) follow-up period, one patient had disease progression. CONCLUSIONS: The majority (90%) of patients with biochemically silent pheochromocytomas developed hemodynamic instability during adrenal surgery. In patients with biochemically silent adrenal lesions and a high suspicion index for pheochromocytoma based on tumor imaging characteristics, pre-operative alpha-blockade treatment may be advisable.

Updating the Landscape for Functioning Gonadotroph Tumors.

Functioning gonadotroph adenomas (FGAs) are rare tumors, as the overwhelming majority of gonadotroph tumors are clinically silent. Literature is based on case reports and small case series. Gonadotroph tumors are poorly differentiated and produce and secrete hormones inefficiently, but in exceptional cases, they cause clinical syndromes due to hypersecretion of intact gonadotropins. The clinical spectrum of endocrine dysfunction includes an exaggerated response of ovaries characterized as ovarian hyperstimulation syndrome (OHSS) in premenopausal females and adolescent girls, testicular enlargement in males, and isosexual precocious puberty in children. Transsphenoidal surgery and removal of tumor reduces hormonal hypersecretion, improves endocrine dysfunction, and provides tissue for further analysis. Medical therapies (somatostatin analogues, dopamine agonists, GnRH agonists/antagonists) are partially or totally ineffective in many cases, especially with respect to antitumor effect. This review aims to update recent literature on these rare functioning tumors and highlight their therapeutic management.

Benefits and Limitations of TKIs in Patients with Medullary Thyroid Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have been used in patients with advanced medullary thyroid carcinoma (MTC); however, data on their effectiveness and safety are limited. The aim of this systematic review and meta-analysis was to document clinical response and toxicities of TKIs in advanced MTC. METHODS: We systematically searched major databases for articles or abstracts on TKI use in MTC patients until May 2018. Objective response (OR), defined as the sum of complete + partial response, expressed as percentage, was our primary endpoint, while disease stability, disease progression (DP), median progression-free survival (PFS), and drug discontinuation rate due to adverse events (AEs) were secondary endpoints. Pooled percentages, PFS time, and 95% CIs were reported. RESULTS: Thirty-three publications were finally included in the analysis: 1 phase IV, 2 phase III trials evaluating vandetanib and cabozantinib, respectively, 20 phase I or II studies, and the remaining 10 studies of retrospective-observational nature. OR was documented in 28.6% (95% CI 25.9-31.9) of patients. Stable disease was recorded in 46.2% (95% CI 43.3-49.1). Overall, DP was observed in 22.9% (95% CI 20.4-27.6). Grade 3 or more AEs occurred in 48.5% (95% CI 45.5-51.5) of patients, and drug discontinuation was reported in 44.7% (95% CI 41.7-47.6). In general, use of TKIs conferred a PFS of 23.3 months (95% CI 21.07-25.5). In particular, vandetanib induced an OR in 33.8% (95% CI 29.6-38.0) of patients and cabozantinib in 27.7% (95% CI 22.05-33.4). DP occurred in 23.7% (95% CI 19.9-27.6) with vandetanib use and in 22.6% (95% CI 17.4-27.9) in cabozantinib-treated patients. Sorafenib, the third most frequently studied drug, showed intermediate efficacy, but higher discontinuation rates. CONCLUSION: Treatment with TKIs in MTC patients with progressive disease is associated with a moderate therapeutic benefit, with achievement of either disease stability or partial response in 73%. The toxicity of these drugs is not negligible, but it is, nonetheless, manageable.

The way toward adulthood for females with nonclassic congenital adrenal hyperplasia.

Females with NC21OHD may present as asymptomatic or develop a wide range of androgen excess expression. Clinical manifestations may become evident in childhood and adolescence and include premature pubarche, precocious puberty, acne, hirsutism, and menstrual disorders or present later in life as oligo-ovulation and infertility. Glucocorticoids have been the mainstay of treatment as they regulate excess androgen expression by dampening ACTH activation. Their use requires a careful dose monitoring to avoid overtreatment and subsequently the risk of obesity, type 2 diabetes, dyslipidemia, hypertension, and osteoporosis. Women with NC21OHD need regular follow up throughout their life in order to overcome the physical and psychological burden of hyperandrogenism.

Mortality of Patients with Cushing's Disease.

Cushing's disease is a rare condition of cortisol excess attributed to a pituitary adenoma with an annual incidence of 1.2-2.4 cases per million population. It is associated with several co-morbidities leading to increased mortality predominantly due to cardiovascular disease. Despite the advances in its diagnosis and management, survival can be compromised even after apparent successful treatment. Minimizing the duration and extent of exposure to hypercortisolaemia by early diagnosis and rapid, effective therapeutic interventions, as well as close monitoring and aggressive control of cardiovascular risk factors are vital for improving outcomes of the patients.

Pituitary dysfunction after traumatic brain injury: prevalence and screening strategies.

INTRODUCTION: Pituitary gland is vulnerable to traumatic brain injury (TBI). As a result a series of neuroendocrine changes appear after head injury; in many occasions they reverse with time, while occasionally new late onset changes may develop. AREAS COVERED: In this review, we focus on the prevalence of anterior and posterior pituitary hormonal changes in the acute and chronic post-TBI period in both children and adults. Moreover, we present evidence supporting the need for evaluating pituitary function along with the current suggestions for the most appropriate screening strategies. We attempted to identify all published literature and we conducted an online search of PubMed, from January 1970 to June 2020. EXPERT OPINION: Adrenal insufficiency and water metabolism disorders are medical emergencies and should be promptly recognized. Awareness for long-term hormonal derangements is necessary, as they may lead to a series of chronic health issues and compromise quality of life. There is a need for well-designed prospective long-term studies that will estimate pituitary function during the acute and chronic phase after head injury.

Clinical evidence of the effect of bisphosphonates on pregnancy and the infant.

Bisphosphonates (BPs) are potent inhibitors of osteoclast mediated bone resorption. These drugs are widely used in the management of osteoporosis and other diseases, characterized by high bone turnover. The effect of BPs on gestation and lactation, when they are used as therapeutic agents in premenopausal women, is yet unknown. We conducted a detailed literature review and identified the cases of BPs use in young women, as well as, the effects of this therapy on the gestation and the embryo. The published data, regarding the use of BPs in premenopausal women and their effects on the pregnancy outcome, are limited. However, we could identify the outcomes of 40 pregnant women, who had received BPs prior to or during pregnancy, that have been documented in the literature. All women had valid indications to receive BPs for serious bone metabolism conditions. We could not identify any prospective trials, which focus on pregnancy outcomes following after the in-utero exposure to BPs. In total, no serious adverse effects were reported. Problems related to the offspring, such as hypocalcemia and a tendency for low body weight (LBW), were self-resolving. In addition, no serious adverse outcomes were reported for women having completed pregnancy. Nevertheless, follow-up was limited for both outcomes suggesting the necessity of national and international registries.

Traumatic brain injury induced neuroendocrine changes: acute hormonal changes of anterior pituitary function.

PURPOSE: It is estimated that approximately 69 million individuals worldwide will sustain a TBI each year, which accounts for substantial morbidity and mortality in both children and adults. TBI may lead to significant neuroendocrine changes, if the delicate pituitary is ruptured. In this review, we focus on the anterior pituitary hormonal changes in the acute post-TBI period and we present the evidence supporting the need for screening of anterior pituitary function in the early post-TBI time along with current suggestions regarding the endocrine assessment and management of these patients. METHODS: Original systematic articles with prospective and/or retrospective design studies of acute TBI were included, as were review articles and case series. RESULTS: Although TBI may motivate an acute increase of stress hormones, it may also generate a wide spectrum of anterior pituitary hormonal deficiencies. The frequency of post-traumatic anterior hypopituitarism (PTHP) varies according to the severity, the type of trauma, the time elapsed since injury, the study population, and the methodology used to diagnose pituitary hormone deficiency. Early neuroendocrine abnormalities may be transient, but additional late ones may also appear during the course of rehabilitation. CONCLUSIONS: Acute hypocortisolism should be diagnosed and managed promptly, as it can be life-threatening, but currently there is no evidence to support treatment of acute GH, thyroid hormones or gonadotropins deficiencies. However, a more comprehensive assessment of anterior pituitary function should be undertaken both in the early and in the post-acute phase, since ongoing hormone deficiencies may adversely affect the recovery and quality of life of these patients.

Association of prolactin receptor (PRLR) variants with prolactinomas.

Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P < 0.0001) in prolactinoma patients than in 60 706 individuals of the Exome Aggregation Consortium cohort and 7045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type (WT) PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms.

A Spontaneous Pregnancy in a Patient with Turner Syndrome with 45,X/47,XXX Mosaicism: A Case Report and Review of the Literature.

BACKGROUND: Turner syndrome is a chromosomal abnormality, due to a total or partial loss of 1 of the X chromosomes and is mostly characterized clinically by short stature and primary ovarian insufficiency. Spontaneous pregnancies are rare (5%) and of relatively high risk. This is 1 of few reported cases of spontaneous conception and favorable prognosis in a patient with Turner syndrome and a 45,X/47,XXX karyotype. CASE: A 21-year-old woman with Turner mosaicism (45,X/47,XXX) who had a full-term, uncomplicated pregnancy after spontaneous conception, gave birth to a healthy female (46,XX) infant. SUMMARY AND CONCLUSION: Spontaneous pregnancies in women with Turner syndrome are a rarity. Fertility preservation methods are being discussed. Due to the high reported incidence of neonatal, obstetric, maternal, and especially cardiovascular complications in those pregnancies, close monitoring is essential.

Epidemiology, clinical presentation and diagnosis of non-functioning pituitary adenomas.

PURPOSE: Non-functioning pituitary adenomas (NFPAs) are benign pituitary neoplasms that do not cause a hormonal hypersecretory syndrome. An improved understanding of their epidemiology, clinical presentation and diagnosis is needed. METHOD: A literature review was performed using Pubmed to identify research reports and clinical case series on NFPAs. RESULTS: They account for 14-54% of pituitary adenomas and have a prevalence of 7-41.3/100,000 population. Their standardized incidence rate is 0.65-2.34/100,000 and the peak occurence is from the fourth to the eighth decade. The clinical spectrum of NFPAs varies from being completely asymptomatic to causing significant hypothalamic/pituitary dysfunction and visual field compromise due to their large size. Most patients present with symptoms of mass effect, such as headaches, visual field defects, ophthalmoplegias, and hypopituitarism but also hyperprolactinaemia due to pituitary stalk deviation and less frequently pituitary apoplexy. Non-functioning pituitary incidentalomas are found on brain imaging performed for an unrelated reason. Diagnostic approach includes magnetic resonance imaging of the sellar region, laboratory evaluations, screening for hormone hypersecretion and for hypopituitarism, and a visual field examination if the lesion abuts the optic nerves or chiasm. CONCLUSION: This article reviews the epidemiology, clinical behaviour and diagnostic approach of non-functioning pituitary adenomas.

Mortality in patients with non-functioning pituitary adenoma.

Non-functioning pituitary adenomas (NFA) are benign pituitary neoplasms not associated with clinical evidence of hormonal hypersecretion. A substantial number of patients with NFA have morbidities related to the tumor and possible recurrence(s), as well as to the treatments offered. Studies assessing the long-term mortality of patients with NFA are limited. Based on the published literature of the last two decades, overall, the standardized mortality ratios in this group suggest mortality higher than that of the general population with deaths attributed mainly to circulatory, respiratory and infectious causes. Women seem to have higher mortality ratios, and assessment of time trends suggests improvement over the years. There is no consensus on predictive factors of mortality but those most consistently identified are older age at diagnosis and high doses of glucocorticoid substitution therapy. Well designed and of adequate power studies are needed to establish the significance of factors compromising the survival of patients with NFA and to facilitate improvements in long-term prognosis.

Outcome of Nonfunctioning Pituitary Adenomas That Regrow After Primary Treatment: A Study From Two Large UK Centers.

Context: Despite the major risk of regrowth of clinically nonfunctioning pituitary adenomas (CNFAs) after primary treatment, systematic data on the probability of further tumor progression and the effectiveness of management approaches are lacking. Objective: To assess the probability of further regrowth(s), predictive factors, and outcomes of management approaches in patients with CNFA diagnosed with adenoma regrowth after primary treatment. Patients, Design, and Setting: Retrospective cohort study of 237 patients with regrown CNFA managed in two UK centers. Results: Median follow-up was 5.9 years (range, 0.4 to 37.7 years). The 5-year second regrowth rate was 35.3% (36.2% after surgery; 12.5% after radiotherapy; 12.7% after surgery combined with radiotherapy; 63.4% with monitoring). Of those managed with monitoring, 34.8% eventually were offered intervention. Type of management and sex were risk factors for second regrowth. Among those with second adenoma regrowth, the 5-year third regrowth rate was 26.4% (24.4% after surgery; 0% after radiotherapy; 0% after surgery combined with radiotherapy; 48.3% with monitoring). Overall, patients with a CNFA regrowth had a 4.4% probability of a third regrowth at 5 years and a 10.0% probability at 10 years; type of management of the first regrowth was the only risk factor. Malignant transformation was diagnosed in two patients. Conclusions: Patients with regrown CNFA after primary treatment continue to carry considerable risk of tumor progression, necessitating long-term follow-up. Management approach to the regrowth was the major factor determining this risk; monitoring had >60% risk of progression at 5 years, and a substantial number of patients ultimately required intervention.

Endocrine sequelae of immune checkpoint inhibitors.

Cancer immunotherapy has introduced a novel class of drugs known as immune checkpoint inhibitors (ICIs). They enhance antitumour immunity by blocking negative regulators (checkpoints) of T cell function that exist on both immune and tumour cells. ICIs targeting CTLA-4 and PD-1/PDL-1 have dramatically changed the outcome of patients with several advanced-stage malignancies but they may lead to a variety of inflammatory toxicities and autoimmune consequences. The main endocrine immune-related adverse events (IRAEs) include hypophysitis, primary thyroid dysfunction, adrenalitis and type 1 diabetes mellitus. In general, the management of endocrine IRAEs requires assessment of their severity, in moderate or severe cases interruption of the checkpoint inhibitor and use of corticosteroid or alternative immunosuppression and appropriate hormone replacement or treatment when necessary.

Mortality in patients with Cushing's disease more than 10 years after remission: a multicentre, multinational, retrospective cohort study.

BACKGROUND: No agreement has been reached on the long-term survival prospects for patients with Cushing's disease. We studied life expectancy in patients who had received curative treatment and whose hypercortisolism remained in remission for more than 10 years, and identified factors determining their survival. METHODS: We did a multicentre, multinational, retrospective cohort study using individual case records from specialist referral centres in the UK, Denmark, the Netherlands, and New Zealand. Inclusion criteria for participants, who had all been in studies reported previously in peer-reviewed publications, were diagnosis and treatment of Cushing's disease, being cured of hypercortisolism for a minimum of 10 years at study entry, and continuing to be cured with no relapses until the database was frozen or death. We identified the number and type of treatments used to achieve cure, and used mortality as our primary endpoint. We compared mortality rates between patients with Cushing's disease and the general population, and expressed them as standardised mortality ratios (SMRs). We analysed survival data with multivariate analysis (Cox regression) with no corrections for multiple testing. FINDINGS: The census dates on which the data were frozen ranged from Dec 31, 2009, to Dec 1, 2014. We obtained data for 320 patients with 3790 person-years of follow-up from 10 years after cure (female:male ratio of 3:1). The median patient follow-up was 11·8 years (IQR 17-26) from study entry and did not differ between countries. There were no significant differences in demographic characteristics, duration of follow-up, comorbidities, treatment number, or type of treatment between women and men, so we pooled data from both sexes for survival analysis. 51 (16%) of the cohort died during follow-up from study entry (10 years after cure). Median survival from study entry was similar for women (31 years; IQR 19-38) and men (28 years; 24-42), and about 40 years (IQR 30-48) from remission. The overall SMR for all-cause mortality was 1·61 (95% CI 1·23-2·12; p=0·0001). The SMR for circulatory disease was increased at 2·72 (1·88-3·95; p<0·0001), but deaths from cancer were not higher than expected (0·79, 0·41-1·51). Presence of diabetes, but not hypertension, was an independent risk factor for mortality (hazard ratio 2·82, 95% CI 1·29-6·17; p=0·0095). We noted a step-wise reduction in survival with increasing number of treatments. Patients cured by pituitary surgery alone had long-term survival similar to that of the general population (SMR 0·95, 95% CI 0·58-1·55) compared with those who were not (2·53, 1·82-3·53; p<0·0001). INTERPRETATION: Patients with Cushing's disease who have been in remission for more than 10 years are at increased risk of overall mortality compared with the general population, particularly from circulatory disease. However, median survival from cure is excellent at about 40 years of remission. Treatment complexity and an increased number of treatments, reflecting disease that is more difficult to control, appears to negatively affect survival. Pituitary surgery alone is the preferred treatment to secure an optimum outcome, and should be done in a centre of surgical excellence. FUNDING: None.

Mortality in patients with non-functioning pituitary adenoma is increased: systematic analysis of 546 cases with long follow-up.

OBJECTIVE: Non-functioning pituitary adenomas (NFAs) have a prevalence of 7-22/100,000 people. A significant number of patients suffer from morbidities related to the tumor, possible recurrence(s), and treatments utilized. Our aim was to assess mortality of patients with macroNFA and predictive factors. DESIGN: Retrospective cohort study in a tertiary referral center in the UK. METHODS: A total of 546 patients operated for a macroNFA between 1963 and 2011 were studied. Mortality data were retrieved through the National Health Service Central Register and hospital records and recorded as standardized mortality ratio (SMR). Mortality was estimated for the total and various subgroups with clinical follow-up data. RESULTS: Median follow-up was 8 years (range: 1 month-48.5 years). SMR was 3.6 (95% CI, 2.9-4.5), for those operated before 1990, 4.7 (95% CI, 2.7-7.6) and for those after 1990, 3.5 (95% CI, 2.8-4.4). Main causes of death were cardio/cerebrovascular (33.7%), infections (30.1%), and malignancy (28.9%). Cox regression analysis demonstrated that only age at diagnosis remained an independent predictor of mortality (hazard ratio 1.10; 95% CI, 1.07-1.13, P<0.001), whereas sex, presentation with acute apoplexy, extent of tumor removal, radiotherapy, recurrence, untreated GH deficiency, FSH/LH deficiency, ACTH deficiency, TSH deficiency, and treatment with desmopressin had no impact. CONCLUSIONS: Despite the improvement of treatments over the last three decades, the mortality of patients with NFAs in our series remains high. Apart from age, factors related with the management/outcome of the tumor are not independent predictors, and pituitary hormone deficits managed with the currently-used substitution protocols do not adversely affect mortality.

Efficacy and complications of pituitary irradiation.

Radiation therapy is widely used in the management of intracranial (including sellar and parasellar) and systemic disorders. Although in many cases the irradiation aims to prevent the growth or regrowth and to control the hormonal hypersecretion of a pituitary tumor, in many others it adversely affects the hypothalamo-pituitary function simply because this area receives significant doses of radiation delivered for non-hypothalamo-pituitary disorders. The main long-term complications include hypopituitarism, optic neuropathy, cerebrovascular morbidity, and second brain tumors. Radiation technique and schedule are important determinants of these adverse effects.

Clinical and biochemical manifestations of Cushing's.

INTRODUCTION: Cushing's syndrome is associated with a number of clinical manifestations and co-morbidities which may not resolve even after long-term remission leading to excessive mortality. MATERIALS AND METHODS: This review summarizes the main manifestations of Cushing's syndrome (active or in remission) with particular focus on data from recently published literature. CONCLUSION: Obesity and metabolic alterations, hypertension and cardio/cerebrovascular complications, hypercoagulability/thromboembolism, neuropsychiatric, muscle/skeletal and immune consequences remain the most challenging. Cardiovascular consequences and immunosuppression determine the main causes of death in Cushing's syndrome necessitating early intervention when possible.