Faculty Bibliography

First-line treatment of endogenous Cushing's syndrome (CS) is surgical removal of the tumor responsible for cortisol excess. However, medical therapy has an established role in treatment when patients are not surgical candidates or decline surgery, residual or recurrent disease is present and not amenable to repeat resection, and control of hypercortisolism is needed either preoperatively or while awaiting the effects of radiotherapy. The approach to medical therapy should be tailored based on the etiology, degree of hypercortisolism, and patient characteristics. Currently available medical therapy for all etiologies of CS either blocks adrenal production of cortisol or blocks its action at the level of the glucocorticoid receptor. Currently available medical therapy for Cushing's disease (CD) targets the adrenocorticotropic hormone-secreting pituitary tumor through activation of somatostatin and dopamine receptors, alkylating DNA damage, or immune system activation. More focused therapy with greater efficacy and fewer adverse effects is needed, particularly in the case of CD, with potential targets and drugs identified and in development.

This Pituitary Society Consensus article presents an evidence-based consensus on the management of pituitary incidentaloma, defined as an unexpected sellar or parasellar finding incidentally discovered on an imaging study that was not performed for a clinically suspected pituitary lesion. Recommendations are offered for when endocrinology, neurosurgery and ophthalmology consultation, dedicated pituitary imaging, pituitary hormone testing and visual assessment are warranted for macroadenomas, microadenomas, cystic lesions and empty sella, as well as when surgical resection is indicated for incidental pituitary adenomas and cystic sellar lesions. Special considerations in patients with multiple endocrine neoplasia type 1, children and adolescents, older people, and pregnant women are addressed. The Consensus workshop concluded that diagnostic and management approaches should be individualized to the specific clinical context of an incidentally discovered pituitary lesion. Consultation with a multidisciplinary pituitary tumour centre of excellence should be considered in the presence of new or deteriorating lesion-specific signs or symptoms, particularly when surgical or other adjuvant interventions are being considered and when there is uncertainty about the most appropriate subsequent management.

PURPOSE/OBJECTIVE:Primary aldosteronism (PA) is an underdiagnosed cause of secondary hypertension with significant health consequences. Expanding screening criteria may improve case detection and reduce the number of untreated patients. METHODS:We assessed PA screening rates in a cohort of 457 adults with comorbid obstructive sleep apnea (OSA) and hypertension (HTN). PA screening in a subset of the cohort (n = 97, 21%) was conducted using serum aldosterone, aldosterone-to-plasma renin activity ratio (ARR), and plasma renin activity (PRA). Screening results were compared between the 2016 Endocrine Society guidelines (serum aldosterone and ARR) and the Vaidya & Carey algorithm (serum aldosterone and PRA). RESULTS:The screened patients were predominantly male (mean age 58.6 years), with common comorbidities including hyperlipidemia (80%) and diabetes mellitus (31%). PA positivity rates differed significantly between screening criteria: 7% tested positive using Endocrine Society guidelines, while 33% screened positive using the Vaidya & Carey algorithm. Notably, 26% of patients with negative screens by Endocrine Society criteria were reclassified as positive, and 11 previously indeterminate cases were classified as negative due to absent renin suppression. Using the Vaidya & Carey algorithm with a stricter PRA suppression threshold, 25% of patients screened positive. CONCLUSION/CONCLUSIONS:The Vaidya & Carey algorithm may be an important tool in increasing detection of previously unidentified cases and clarifying the diagnosis of cases that were previously deemed indeterminate. Given the morbidity of untreated PA, more robust screening approaches are warranted. Prospective studies are needed to validate these findings across diverse populations.

The neurocognitive and psychiatric effects of Cushing's syndrome (CS) are well recognized and negatively impact quality of life. The aim of this systematic review is to compare neurocognitive disease, psychiatric symptoms, and structural brain changes in patients with Cushing's disease (CD)/CS and those with non-functioning pituitary adenoma (NFPA), both before and after surgical treatment, and in comparison to healthy controls. Possible predictors of persistent neurocognitive symptoms and reduced quality of life in patients with CS are highlighted. We reviewed the English literature published in Medline/Pubmed until 2021 to identify eligible studies. This systematic review was registered on Prospero and reported following the PRISMA statement guidelines. The initial literature search yielded 1772 articles, of which 1096 articles remained after removing duplicates. After excluding case reports, animal studies, narrative reviews, comparative reviews, and articles not in English, 86 papers underwent full-text review. Studies eligible for inclusion met the following criteria: (1) described patients with CD/CS, (2) reports of psychiatric symptoms, (3) written in English or with available English translation, and (4) published in a peer-reviewed journal. The full-text review process identified 40 eligible studies. The 40 studies included a total of 2603 participants with CD or CS, with 45.2% of the total participants having CD. The majority of studies were case-control studies and used validated questionnaires such as the Beck's Depression Index, Trail Making Test, Hospital Anxiety and Depression Scale, and Cushing Quality of Life for screening. Compared to NFPA controls, patients with CD who had greater baseline serum cortisol levels had worse cognitive function, even after surgical remission. This suggests a possible association between greater baseline cortisol levels in patients with CS and persistent cognitive impairment. A longer duration of uncontrolled CS was associated with worse cognitive function; however, there was no association found between the length of remission and memory. Overall brain volume was increased in patients in remission from CD compared to active disease. However, temporal and frontal lobe volumes did not recover to normal volumes. Patients with CS experience neurocognitive dysfunction, psychiatric disorders, and diminished quality of life, and symptoms may persist after curative surgery. We found several factors consistently associated with persistent cognitive and neuropsychiatric symptoms in patients with CS including higher pre-operatively baseline cortisol production, longer duration of disease, frontal and temporal lobe atrophy, and the presence of cognitive and neuropsychiatric symptoms at baseline. Larger prospective studies are required to validate these findings.

Craniopharyngiomas are histologically benign central nervous system tumors derived from embryonic epithelial cells of Rathke's pouch. The disease demonstrates a bimodal age distribution, occurring most often in patients 5-14 and 50-74 years of age. Common comorbidities include hypopituitarism, hypothalamic obesity, sleep apnea, visual impairment and neurocognitive disturbances. There are several key differences in the presentation, tumor characteristics and clinical outcomes between age groups. Childhood craniopharyngiomas are mostly adamantinomatous and often present as larger tumors with worse functional outcomes such as rates of obesity and neurological deficits. Adults experience similar but slightly adjusted rates of comorbidity with both the adamantinomatous and papillary subtypes. This review presents a case-based discussion of adult craniopharyngiomas, focusing on recent literature regarding their presentation, pathology and pathogenesis, diagnosis, treatment and long-term sequelae.

BACKGROUND/UNASSIGNED:Acromegaly is a rare endocrine disorder characterized by chronic excess growth hormone (GH) and elevated insulin-like growth factor-1 (IGF-1), which are known to have mitogenic and anti-apoptotic effects on breast tissue. While an increased risk of several malignancies has been observed in patients with acromegaly, the relationship between acromegaly and breast cancer remains unclear. OBJECTIVE/UNASSIGNED:To systematically evaluate the incidence and prevalence of breast cancer in patients with acromegaly and assess whether a consistent oncologic risk exists in this population. METHODS/UNASSIGNED:We systematically searched PubMed, EMBASE, and Web of Science from inception through early 2025 for studies reporting breast cancer in acromegaly. Citation tracking identified additional reports. After screening, 24 studies (>17,000 patients) were included, with data on cancer frequency, timing, and GH/IGF-1 levels extracted for analysis. From a subset of these studies reporting standardized incidence ratios (SIR) with 95% confidence intervals (CIs), a random-effects meta-analysis was performed to generate a pooled SIR, accounting for between-study heterogeneity. RESULTS/UNASSIGNED:This systematic review of 24 studies with diverse designs, encompassing 17,413 patients with acromegaly, found breast cancer prevalence ranging from 0.42% to 5.85%. Several studies reported elevated GH and IGF-1 levels at any cancer diagnosis, but methodological heterogeneity limited conclusions on dose-response or temporal associations. Ten studies reported SIRs with 95% CIs and were included in the pooled analysis. The pooled SIR for breast cancer among patients with acromegaly was 1.20 (95% CI: 0.94-1.54), with moderate heterogeneity (I² = 58%). CONCLUSION/UNASSIGNED:Although there is a strong biological rationale for a link between GH/IGF-1 excess and breast cancer, current clinical studies have not shown a clear or consistently increased risk in patients with acromegaly. The mixed results likely reflect issues such as surveillance bias, differences in study designs, and limited adjustment for confounders. For now, breast cancer screening in this population should generally follow the same guidelines as the general population, with perhaps closer attention in patients who have poorly controlled disease. Moving forward, well-designed prospective studies that track cancer outcomes in relation to biochemical disease activity and control will be key to answering this question.

The first-line treatment for Cushing's disease is transsphenoidal adenomectomy, which can be curative in a significant number of patients. The second-line options in cases of failed primary pituitary surgery include repeat surgery, medical therapy, and radiation. The role for medical therapy has expanded in the last decade, and options include pituitary-targeting drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. Bilateral adrenalectomy is a more aggressive approach, which may be necessary in cases of persistent hypercortisolism despite surgery, medical treatment, or radiation or when rapid normalization of cortisol is needed. We review the available treatment options for Cushing's disease, focusing on the second-line treatment options to consider after failed primary pituitary surgery.

UNLABELLED:Acromegaly is a rare endocrine disorder caused by hypersecretion of growth hormone (GH) from a pituitary adenoma. Elevated GH levels stimulate excess production of insulin-like growth factor 1 (IGF-1) which leads to the insidious onset of clinical manifestations. The most common primary central nervous system (CNS) tumors, meningiomas originate from the arachnoid layer of the meninges and are typically benign and slow-growing. Meningiomas are over twice as common in women as in men, with age-adjusted incidence (per 100,000 individuals) of 10.66 and 4.75, respectively. Several reports describe co-occurrence of meningiomas and acromegaly. We aimed to determine whether patients with acromegaly are at elevated risk for meningioma. Investigation of the literature showed that co-occurrence of a pituitary adenoma and a meningioma is a rare phenomenon, and the majority of cases involve GH-secreting adenomas. To the best of our knowledge, a systematic review examining the association between meningiomas and elevated GH levels (due to GH-secreting adenomas in acromegaly or exposure to exogenous GH) has never been conducted. The nature of the observed coexistence between acromegaly and meningioma -whether it reflects causation or mere co-association -is unclear, as is the pathophysiologic etiology. SYSTEMATIC REVIEW REGISTRATION/UNASSIGNED:https://www.crd.york.ac.uk/prospero/, identifier CRD42022376998.