Faculty Bibliography

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.

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.

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.

BACKGROUND:There is a bidirectional association between primary aldosteronism and obstructive sleep apnea, with evidence suggesting that the treatment of primary aldosteronism can reduce obstructive sleep apnea severity. Current guidelines recommend screening for primary aldosteronism in patients with comorbid hypertension and obstructive sleep apnea, identifying potential candidates for treatment. However, emerging data suggest current screening practices are unsatisfactory. Moreover, data regarding the true incidence of primary aldosteronism among this population are limited. This study aimed to assess the primary aldosteronism screening rate among patients with obstructive sleep apnea and hypertension at our institution and estimate the prevalence of primary aldosteronism among this population. METHODS:Sleep studies conducted at our institution between January and September 2021 were retrospectively reviewed. Adult patients with a sleep study diagnostic of obstructive sleep apnea (respiratory disturbance index ≥5) and a diagnosis of hypertension were included. Patient medical records were reviewed and laboratory data of those with biochemical screening for primary aldosteronism were assessed by an experienced endocrinologist. Screening rates were compared before and after initiation of a screening protocol in accordance with the 2016 Endocrine Society guidelines. RESULTS:A total of 1,005 patients undergoing sleep studies were reviewed; 354 patients had comorbid obstructive sleep apnea and hypertension. Patients were predominantly male (67%), with a mean age of 58 years (standard deviation = 12.9) and mean body mass index of 34 (standard deviation = 8.1). The screening rate for primary aldosteronism among included patients was 19% (n = 67). The screening rate was significantly higher after initiation of a dedicated primary aldosteronism screening protocol (23% vs 12% prior; P = .01). Fourteen screens (21%) were positive for primary aldosteronism, whereas 45 (67%) were negative and 8 (12%) were indeterminate. Four had prior abdominal cross-sectional imaging, with 3 revealing an adrenal adenoma. Compared with patients without primary aldosteronism, patients with positive primary aldosteronism screens were more likely to have a history of hypokalemia (36% vs 4.4%; P = .002). The frequency of hyperlipidemia, diabetes mellitus, and left ventricular hypertrophy did not differ between patients with positive versus negative screens. CONCLUSION/CONCLUSIONS:Current screening practices for primary aldosteronism among patients with comorbid obstructive sleep apnea and hypertension are suboptimal. Patients evaluated at sleep centers may represent an optimal population for screening, as the prevalence of primary aldosteronism among this cohort appears high.

Endogenous Cushing's syndrome (CS) is a rare disease characterized by prolonged glucocorticoid excess. Timely diagnosis is critical to allow prompt treatment and limit long-term disease morbidity and risk for mortality. Traditional biochemical diagnostic modalities each have limitations and sensitivities and specificities that vary significantly with diagnostic cutoff values. Biochemical evaluation is particularly complex in patients whose hypercortisolemia fluctuates daily, often requiring repetition of tests to confirm or exclude disease, and when delineating CS from physiologic, nonneoplastic states of hypercortisolism. Lastly, traditional pituitary MRI may be negative in up to 60% of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (termed "Cushing's disease" [CD]) whereas false positive pituitary MRI findings may exist in patients with ectopic ACTH secretion. Thus, differentiating CD from ectopic ACTH secretion may necessitate dynamic testing or even invasive procedures such as bilateral inferior petrosal sinus sampling. Newer methods may relieve some of the diagnostic uncertainty in CS, providing a more definitive diagnosis prior to subjecting patients to additional imaging or invasive procedures. For example, a novel method of cortisol measurement in patients with CS is scalp hair analysis, a non-invasive method yielding cortisol and cortisone values representing long-term glucocorticoid exposure of the past months. Hair cortisol and cortisone have both shown to differentiate between CS patients and controls with a high sensitivity and specificity. Moreover, advances in imaging techniques may enhance detection of ACTH-secreting pituitary adenomas. While conventional pituitary MRI may fail to identify microadenomas in patients with CD, high-resolution 3T-MRI with 3D-spoiled gradient-echo sequence has thinner sections and superior soft-tissue contrast that can detect adenomas as small as 2 mm. Similarly, functional imaging may improve the identification of ACTH-secreting adenomas noninvasively; Gallium-68-tagged corticotropin-releasing hormone (CRH) combined with PET-CT can be used to detect CRH receptors, which are upregulated on corticotroph adenomas. This technique can delineate functionality of adenomas in patients with CD from patients with ectopic ACTH secretion and false positive pituitary lesions on MRI. Here, we review emerging methods and imaging modalities for the diagnosis of CS, discussing their diagnostic accuracy, strengths and limitations, and applicability to clinical practice.

Cushing's syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing's syndrome) or autonomous cortisol overproduction, whether or not adrenocorticotropin hormone (ACTH) dependent (endogenous Cushing's syndrome). An early diagnosis of Cushing's syndrome is warranted, however, in clinical practice very challenging partly due to resemblance with other common conditions (i.e. pseudo-Cushing's syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing's syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing's syndrome. Interpretation of results can be difficult due to individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing's syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80-85%) or ACTH-independent (15-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of 'Approach to the patient' the diagnostic workup of Cushing's syndrome is discussed with answering the questions when to screen, how to screen and how to differentiate the different causes. In this respect, latest developments in biochemical and imaging techniques are discussed as well.