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.

Increased risk of non-alcoholic fatty liver disease in women with gestational diabetes mellitus: A population-based cohort study, systematic review and meta-analysis.

AIMS: Non-Alcoholic Fatty Liver Disease (NAFLD) is one of the leading causes of liver transplantation in the West. This study seeks to examine whether women with gestational diabetes mellitus (GDM) are at increased risk of developing NAFLD compared to women without GDM. METHODS: We conducted a population-based retrospective matched-controlled cohort study utilising The Health Improvement Network (THIN), a large primary care database representative of the United Kingdom population, between 01/01/1990 to 31/05/2016 followed by systematic review of available literature. The study population included 9640 women with GDM and 31,296 controls without GDM, matched for age, body mass index (BMI) and time of pregnancy. All study participants were free from NAFLD diagnosis at study entry. Patients with GDM and patients developing NAFLD were identified by clinical codes. RESULTS: The median (range) follow-up duration was similar in women with and without GDM (2.95 (1.21-6.01) vs 2.85 (1.14-5.75) years respectively). Unadjusted incidence rate ratio (IRR) for NAFLD development in women with vs without GDM was 3.28 (95% CI 2.14-5.02), which remained significant after adjustment for wide range of potential confounders (IRR 2.70; 95% CI 1.744-4.19). The risk of NAFLD in GDM remained high (IRR 2.46: 95% CI 1.51-4.00) despite women being censored after they developed type 2 diabetes. The meta-analysis of 3 studies (including the current study) showed increased NAFLD risk in women with vs without GDM (OR 2.60; 95% CI 1.90-3.57, I2 = 0%). As our study is based on routine clinical diagnosis of NAFLD, this study could potentially have underestimated the risk of NAFLD development. CONCLUSIONS: Women with GDM are at increased risk of developing NAFLD in their later life compared to women without GDM regardless of the development of type 2 diabetes. Clinicians should have a low threshold to investigate women with history of GDM for the presence of NAFLD. Further studies to identify screening strategies are needed.

MECHANISMS OF ENDOCRINOLOGY: Mechanisms of disease: the endocrinology of obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is a common disorder that is associated with serious comorbidities with a negative impact on quality of life, life expectancy and health costs. As OSA is related to obesity and is associated with sleep disruption, increased inflammation and oxidative stress, it is not surprising that OSA has an impact on the secretion of multiple hormones and is implicated in the development of many endocrine conditions. On the other hand, many endocrine conditions that can affect obesity and/or upper airways anatomy and stability have been implicated in the development or worsening of OSA. This bidirectional relationship between OSA and the endocrine system has been increasingly recognised in experimental and epidemiological studies and there are an increasing number of studies examining the effects of OSA treatment on endocrine conditions and vice versa. In this review article, we will critically appraise and describe the impact of OSA on the endocrine system including obesity, dysglycaemia, the pituitary, the thyroid, the adrenals, the reproductive system and the bones. In each section, we will assess whether a bidirectional relationship exists, and we will describe the potential underlying mechanisms. We have focused more on recent studies and randomised controlled trials where available and attempted to provide the information within clinical context and relevance.

Recurrence in silent corticotroph adenomas after primary treatment: A systematic review and meta-analysis.

CONTEXT: 2017 WHO Classification of Pituitary Tumors grades silent corticotroph adenomas (SCAs) as "high-risk adenomas" due to their aggressive clinical behavior (high probability of recurrence). However, studies comparing recurrence rates of SCAs with other non-functioning pituitary adenoma (NFPAs) subtypes have provided conflicting results. OBJECTIVE: Estimate recurrence rates of SCAs after primary treatment (surgery±radiotherapy) and recurrence rate ratios (RRR) between SCAs and other NFPA subtypes. METHODS: Systematic review of published literature reporting on outcomes of SCAs up to October 31, 2017 was conducted. Recurrence rates, RRRs, 95% confidence intervals (CIs) were estimated from each study and pooled using random effects meta-analysis model. RESULTS: For determination of SCAs recurrence rates, 14 studies (low risk of bias, 297 patients) were selected; recurrence rate was 5.96 (95% CI, 4.3-7.84) per 100 person-years. Based on studies with mean follow-up <5 or ≥5 years, 25% (cumulative incidence 0.25; 95% CI, 0.13-0.38) and 31% (cumulative incidence 0.31; 95% CI, 0.23-0.40) of SCAs had recurrence, respectively. Recurrence rates after surgery or surgery+radiotherapy were 5.41 (95% CI, 3.28-7.96) and 4.88 (95% CI, 0.67-11.54) cases per 100 person-years, respectively. Analysis of 10 eligible studies (moderate risk of bias, 244 SCAs, 1622 NFPAs) showed no significant RRR (1.44; 95% CI, 0.9-2.33, p=0.130) between the groups. Focus on tumors treated solely by surgery also revealed no significant RRR (1.17; 95% CI, 0.79-1.75, p=0.429). CONCLUSIONS: Based on studies with mean follow-up ≥5 years, 31% of SCAs have recurrence. No evidence supporting higher recurrence risk of SCAs compared with other NFPA subtypes was found.

Epidemiology of acromegaly: review of population studies.

Acromegaly is a rare condition necessitating large population studies for the generation of reliable epidemiological data. In this review, we systematically analysed the epidemiological profile of this condition based on recently published population studies from various geographical areas. The total prevalence ranges between 2.8 and 13.7 cases per 100,000 people and the annual incidence rates range between 0.2 and 1.1 cases/100,000 people. The median age at diagnosis is in the fifth decade of life with a median diagnostic delay of 4.5-5 years. Acral enlargement and coarse facial features are the most commonly described clinical manifestations. At the time of detection, most of the tumors are macroadenomas possibly relating to diagnostic delays and posing challenges in the surgical management. Increased awareness of acromegaly amongst the medical community is of major importance aiming to reduce the adverse sequelae of late diagnosis and treatment, improve patient outcomes and, hopefully, reduce the burden on the health care system.